Fused compounds that inhibit vanilloid subtype 1 (VR1) receptor

ABSTRACT

Compounds of formula (I)  
                 
are novel VR1 antagonists that are useful in treating pain, inflammatory thermal hyperalgesia, urinary incontinence, or bladder overactivity.

This application is a divisional of U.S. Ser. No. 10/459,925 filed Jun.12, 2003, from which priority is claimed pursuant to 35 U.S.C. § 120 andwhich is incorporated herein by reference in its entirety.

TECHNICAL BACKGROUND

The present invention relates to compounds of formula (I), which areuseful for treating disorders caused by or exacerbated by vanilloidreceptor activity and pharmaceutical compositions containing compoundsof formula (I). The compounds of the present invention are useful intreating pain, bladder overactivity, or urinary incontinence.

BACKGROUND OF INVENTION

Nociceptors are primary sensory afferent (C and Aδ fibers) neurons thatare activated by a wide variety of noxious stimuli including chemical,mechanical, thermal, and proton (pH<6) modalities. The lipophillicvanilloid, capsaicin, activates primary sensory fibers via a specificcell surface capsaicin receptor, cloned as VR1. The intradermaladministration of capsaicin is characterized by an initial burning orhot sensation followed by a prolonged period of analgesia. The analgesiccomponent of VR1 receptor activation is thought to be mediated by acapsaicin-induced desensitization of the primary sensory afferentterminal. Thus, the long lasting anti-nociceptive effects of capsaicinhas prompted the clinical use of capsaicin analogs as analgesic agents.Further, capsazepine, a capsaicin receptor antagonist can reduceinflammation-induced hyperalgesia in animal models. VR1 receptors arealso localized on sensory afferents which innervate the bladder.Capsaicin or resiniferatoxin has been shown to ameliorate incontinencesymptoms upon injection into the bladder.

The VR1 receptor has been called a “polymodal detector” of noxiousstimuli since it can be activated in several ways. The receptor channelis activated by capsaicin and other vanilloids and thus is classified asa ligand-gated ion channel. VR1 receptor activation by capsaicin can beblocked by the competitive VR1 receptor antagonist, capsazepine. Thechannel can also be activated by protons. Under mildly acidic conditions(pH 6-7), the affinity of capsaicin for the receptor is increased,whereas at pH<6, direct activation of the channel occurs. In addition,when membrane temperature reaches 43° C., the channel is opened. Thusheat can directly gate the channel in the absence of ligand. Thecapsaicin analog, capsazepine, which is a competitive antagonist ofcapsaicin, blocks activation of the channel in response to capsaicin,acid, or heat.

The channel is a nonspecific cation conductor. Both extracellular sodiumand calcium enter through the channel pore, resulting in cell membranedepolarization. This depolarization increases neuronal excitability,leading to action potential firing and transmission of a noxious nerveimpulse to the spinal cord. In addition, depolarization of theperipheral terminal can lead to release of inflammatory peptides suchas, but not limited to, substance P and CGRP, leading to enhancedperipheral sensitization of tissue.

Recently, two groups have reported the generation of a “knock-out” mouselacking the VR1 receptor (VR1(−/−)). Electrophysiological studies ofsensory neurons (dorsal root ganglia) from these animals revealed amarked absence of responses evoked by noxious stimuli includingcapsaicin, heat, and reduced pH. These animals did not display any overtsigns of behavioral impairment and showed no differences in responses toacute non-noxious thermal and mechanical stimulation relative towild-type mice. The VR1 (−/−) mice also did not show reduced sensitivityto nerve injury-induced mechanical or thermal nociception. However, theVR1 knock-out mice were insensitive to the noxious effects ofintradermal capsaicin, exposure to intense heat (50-55° C.), and failedto develop thermal hyperalgesia following the intradermal administrationof carrageenan.

The compounds of the present invention are novel VR1 antagonists andhave utility in treating pain, bladder overactivity, or urinaryincontinence.

SUMMARY OF THE PRESENT INVENTION

The present invention discloses novel compounds, a method for inhibitingthe VR1 receptor in mammals using these compounds, a method forcontrolling pain in mammals, and pharmaceutical compositions includingthose compounds. More particularly, the present invention is directed tocompounds of formula (I)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

-   -   --- is absent or a single bond;    -   X₁ is N or CR₁;    -   X₂ is N or CR₂;    -   X₃ is N, NR₃, or CR₃;    -   X₄ is a bond, N, or CR₄;    -   X₅ is N or C;    -   provided that at least one of X₁, X₂, X₃, and X₄ is N;    -   Z₁ is O, NH, or S;    -   Z₂ is a bond, NH, or O;    -   Ar₁ is dihydro-1H-indenyl, 1H-indenyl, tetrahydronaphthalenyl,        or dihydronaphthalenyl, wherein the Ar₁ group is optionally        substituted with 1, 2, 3, 4, or 5 substituents independently        selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,        alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl,        alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl,        carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl,        haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy,        hydroxyalkyl, mercapto, mercaptoalkyl, nitro, (CF₃)₂(HO)C—,        —NR_(A)S(O)₂R_(B), —S(O)₂OR_(A), —S(O)₂R_(B), —NZ_(A)Z_(B),        (NZ_(A)Z_(B))alkyl, (NZ_(A)Z_(B))carbonyl,        (NZ_(A)Z_(B))carbonylalkyl, or (NZ_(A)Z_(B))sulfonyl, wherein        Z_(A) and Z_(B) are each independently hydrogen, alkyl,        alkylcarbonyl, formyl, aryl, or arylalkyl;    -   R₁, R₃, R₅, R₆, and R₇ are each independently hydrogen, alkenyl,        alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,        alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl,        alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl,        cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl,        formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen,        hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro,        (CF₃)₂(HO)C—, —NR_(A)S(O)₂R_(B), —S(O)₂OR_(A), —S(O)₂R_(B),        —NZ_(A)Z_(B), (NZ_(A)Z_(B))alkyl, (NZ_(A)Z_(B))carbonyl,        (NZ_(A)Z_(B))carbonylalkyl or (NZ_(A)Z_(B))sulfonyl;    -   R₂ and R₄ are each independently hydrogen, alkenyl, alkoxy,        alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,        alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy,        alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl,        cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, haloalkoxy,        haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl,        mercapto, mercaptoalkyl, nitro, (CF₃)₂(HO)C—, —NR_(A)S(O)₂R_(B),        —S(O)₂OR_(A), —S(O)₂R_(B), —NZ_(A)Z_(B), (NZ_(A)Z_(B))alkyl,        (NZ_(A)Z_(B))alkylcarbonyl, (NZ_(A)Z_(B))carbonyl,        (NZ_(A)Z_(B))carbonylalkyl, (NZ_(A)Z_(B))sulfonyl,        (NZ_(A)Z_(B))C(═NH)—, (NZ_(A)Z_(B))C(═NCN)NH—, or        (NZ_(A)Z_(B))C(═NH)NH—;    -   R_(A) is hydrogen or alkyl;    -   R_(B) is alkyl, aryl, or arylalkyl;    -   R_(8a) is hydrogen or alkyl; and    -   R_(8b) is absent, hydrogen, alkoxy, alkoxycarbonylalkyl, alkyl,        alkylcarbonyloxy, alkylsulfonyloxy, halogen, or hydroxy;    -   provided that R_(8b) is absent when X₅ is N.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

In the principle embodiment, compounds of formula (I) are disclosed

or a pharmaceutically acceptable salt or prodrug thereof, wherein

-   -   --- is absent or a single bond;    -   X₁ is N or CR₁;    -   X₂ is N or CR₂;    -   X₃ is N, NR₃, or CR₃;    -   X₄ is a bond, N, or CR₄;    -   X₅ is N or C;    -   provided that at least one of X₁, X₂, X₃, and X₄ is N;    -   Z₁ is O, NH, or S;    -   Z₂ is a bond, NH, or O;    -   Ar₁ is dihydro-1H-indenyl, 1H-indenyl, tetrahydronaphthalenyl,        or dihydronaphthalenyl, wherein the Ar₁ group is optionally        substituted with 1, 2, 3, 4, or 5 substituents independently        selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,        alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl,        alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl,        carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl,        haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy,        hydroxyalkyl, mercapto, mercaptoalkyl, nitro, (CF₃)₂(HO)C—,        —NR_(A)S(O)₂R_(B), —S(O)₂OR_(A), —S(O)₂R_(B), —NZ_(A)Z_(B),        (NZ_(A)Z_(B))alkyl, (NZ_(A)Z_(B))carbonyl,        (NZ_(A)Z_(B))carbonylalkyl or (NZ_(A)Z_(B))sulfonyl, wherein        Z_(A) and Z_(B) are each independently hydrogen, alkyl,        alkylcarbonyl, formyl, aryl, or arylalkyl;    -   R₁, R₃, R₅, R₆, and R₇ are each independently hydrogen, alkenyl,        alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,        alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl,        alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl,        cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl,        formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen,        hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro,        (CF₃)₂(HO)C—, —NR_(A)S(O)₂R_(B), —S(O)₂OR_(A), —S(O)₂R_(B),        —NZ_(A)Z_(B), (NZ_(A)Z_(B))alkyl, (NZ_(A)Z_(B))carbonyl,        (NZ_(A)Z_(B))carbonylalkyl or (NZ_(A)Z_(B))sulfonyl;    -   R₂ and R₄ are each independently hydrogen, alkenyl, alkoxy,        alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,        alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy,        alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl,        cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, haloalkoxy,        haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl,        mercapto, mercaptoalkyl, nitro, (CF₃)₂(HO)C—, —NR_(A)S(O)₂R_(B),        —S(O)₂OR_(A), —S(O)₂R_(B), —NZ_(A)Z_(B), (NZ_(A)Z_(B))alkyl,        (NZ_(A)Z_(B))alkylcarbonyl, (NZ_(A)Z_(B))carbonyl,        (NZ_(A)Z_(B))carbonylalkyl, (NZ_(A)Z_(B))sulfonyl,        (NZ_(A)Z_(B))C(═NH)—, (NZ_(A)Z_(B))C(═NCN)NH—, or        (NZ_(A)Z_(B))C(═NH)NH—;    -   R_(A) is hydrogen or alkyl;    -   R_(B) is alkyl, aryl, or arylalkyl;    -   R_(8a) is hydrogen or alkyl; and    -   R_(8b) is absent, hydrogen, alkoxy, alkoxycarbonylalkyl, alkyl,        alkylcarbonyloxy, alkylsulfonyloxy, halogen, or hydroxy;    -   provided that R_(8b) is absent when X₅ is N.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is a single bond; X₁ is CR₁; X₂ is CR₂; X₄ isCR; X₃ and X₅ are N; Z₁ is O; Z₂ is NH; Ar₁ is dihydro-1H-indenyloptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylthio, alkynyl, carboxy, cyano, haloalkoxy,haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, ornitro; R_(8b) is absent; and R₁, R₂, R₄, R₅, R₆, R₇, and R_(8a) are asdefined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is a single bond; X₁ is CR₁; X₂ is CR₂; X₄ isCR₄; X₃ and X₅ are N; Z₁ is O; Z₂ is NH; Ar₁ is dihydro-1H-indenyloptionally substituted with 1 or 2 substituents independently selectedfrom alkyl, haloalkyl, or halogen; R_(8b) is absent; and R₁, R₂, R₄, R₅,R₆, R₇, and R_(8a) are as defined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is a single bond; X₁ is CR₁; X₂ is CR₂; X₄ isCR₄; X₃ and X₅ are N; Z₁ is O; Z₂ is NH; Ar₁ is 2,3-dihydro-1H-indenyloptionally substituted with 1 or 2 substituents independently selectedfrom alkyl, haloalkyl, or halogen; R_(8b) is absent; R₁, R₄, R₅, R₆, R₇,and R_(8a) are hydrogen; and R₂ is hydrogen or alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is a single bond; X₁ is CR₁; X₂ is CR₂; X₄ isCR₄; X₃ and X₅ are N; Z₁ is O; Z₂ is NH; Ar₁ is2,3-dihydro-1H-inden-1-yl substituted with 1 or 2 substituentsindependently selected from alkyl, haloalkyl, halogen, or heterocyclewherein the heterocycle is 1-piperidinyl or hexahydro-1H-azepin-1-yl;R₁, R₄, R₅, R₆, R₇, and R_(8a) are hydrogen; R₂ is hydrogen or alkyl;and R_(8b) is absent.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is a single bond; X₁ is CR₁; X₂ is CR₂; X₄ isCR₄; X₃ and X₅ are N; Z₁ is O; Z₂ is NH; Ar₁ is2,3-dihydro-1H-inden-2-yl substituted with 1 or 2 substituentsindependently selected from alkyl, haloalkyl, halogen, or heterocyclewherein the heterocycle is 1-piperidinyl or hexahydro-1H-azepin-1-yl;R₁, R₄, R₅, R₆, R₇, and R_(8a) are hydrogen; R₂ is hydrogen or alkyl;and R_(8b) is absent.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; X₅ is N; Z₁ is O; Z₂ is NH; Ar₁ is 2,3-dihydro-1H-inden-1-yloptionally substituted with 1 or 2 substituents independently selectedfrom alkyl, haloalkyl, halogen, or heterocycle; Rb is absent; and R₁,R₃, R₅, R₆, R₇, and R_(8a) are as defined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; X₅ is N; Z₁ is O; Z₂ is NH; Ar₁ is 2,3-dihydro-1H-inden-1-yloptionally substituted with 1 or 2 substituents independently selectedfrom alkyl, haloalkyl, halogen, or heterocycle wherein the heterocycleis piperidinyl or hexahydro-1H-azepinyl; R₃ is hydrogen; R_(8b) isabsent; and R₁, R₅, R₆, R₇, and R_(8a) are as defined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; X₅ is N; Z₁ is O; Z₂ is NH; Ar₁ is 2,3-dihydro-1H-inden-1-yloptionally substituted with 1 or 2 substituents independently selectedfrom alkyl, haloalkyl, halogen, or heterocycle wherein the heterocycleis piperidinyl or hexahydro-1H-azepinyl; R₃ is hydrogen; R_(8b) isabsent; and R₁, R₅, R₆, R₇, and R_(8a) are hydrogen.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; X₅ is N; Z₁ is O; Z₂ is NH; Ar₁ is 2,3-dihydro-1H-inden-1-yloptionally substituted with 1 alkyl substituent wherein a preferredalkyl is tert-butyl; R₃ is hydrogen; R_(8b) is absent; and R₁, R₅, R₆,R₇, and R_(8a) are hydrogen.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; X₅ is N; Z₁ is O; Z₂ is NH; Ar₁ is 2,3-dihydro-1H-inden-1-yloptionally substituted with 1 heterocycle substituent wherein apreferred heterocycle is 1-piperidinyl or hexahydro-1H-azepin-1-yl; R₃is hydrogen; R_(8b) is absent; and R₁, R₅, R₆, R₇, and R_(8a) arehydrogen.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; X₅ is N; Z₁ is O; Z₂ is NH; Ar₁ is 2,3-dihydro-1H-inden-1-yloptionally substituted with 1 haloalkyl substituent wherein a preferredhaloalkyl is trifluoromethyl; R₃ is hydrogen; R_(8b) is absent; and R₁,R₅, R₆, R₇, and R_(8a) are hydrogen.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; Z₁ is O; Z₂ is NH; Ar₁ is 2,3-dihydro-1H-inden-1-yloptionally substituted with 1 or 2 substituents independently selectedfrom alkyl, haloalkyl, halogen, or heterocycle wherein the heterocycleis piperidinyl or hexahydro-1H-azepinyl; R₃ is alkoxycarbonyl; R_(8b) isabsent; and R₁, R₅, R₆, R₇, and R_(8a) are as defined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; Z₁ is O; Z₂ is NH; Ar₁ is 2,3-dihydro-1H-inden-1-yloptionally substituted with 1 or 2 substituents independently selectedfrom alkyl, haloalkyl, halogen, or heterocycle wherein the heterocycleis piperidinyl or hexahydro-1H-azepinyl; R₃ is alkoxycarbonyl wherein apreferred alkoxycarbonyl is methylcarbonyl, ethylcarbonyl,isopropylcarbonyl, or isobutylcarbonyl; R_(8b) is absent; and R₁, R₅,R₆, R₇, and R_(8a) are hydrogen.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; Z₁ is O; Z₂ is NH; Ar₁ is 2,3-dihydro-1H-inden-1-yloptionally substituted with 1 alkyl substituent wherein a preferredalkyl is tert-butyl; R₃ is alkoxycarbonyl wherein a preferredalkoxycarbonyl is methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, orisobutylcarbonyl; R_(8b) is absent; and R₁, R₅, R₆, R₇, and R_(8a) arehydrogen.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; Z₁ is O; Z₂ is NH; Ar₁ is 2,3-dihydro-1H-inden-1-yloptionally substituted with 1 haloalkyl substituent wherein a preferredhaloalkyl is trifluoroalkyl; R₃ is alkoxycarbonyl wherein a preferredalkoxycarbonyl is methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, orisobutylcarbonyl; R_(8b) is absent; and R₁, R₅, R₆, R₇, and R_(8a) arehydrogen.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; Z₁ is O; Z₂ is NH; Ar₁ is 2,3-dihydro-1H-inden-1-yloptionally substituted with 1 heterocycle substituent wherein apreferred heterocycle is 1-piperidinyl or hexahydro-1H-azepin-1-yl; R₃is alkoxycarbonyl wherein a preferred alkoxycarbonyl is methylcarbonyl,ethylcarbonyl, isopropylcarbonyl, or isobutylcarbonyl; R_(8b) is absent;and R₁, R₅, R₆, R₇, and R_(8a) are hydrogen.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; X₅ is N; Z₁ is O; Z₂ is NH; Ar₁ is 2,3-dihydro-1H-inden-2-yloptionally substituted with 1 or 2 substituents independently selectedfrom alkyl, haloalkyl, halogen, or heterocycle wherein the heterocycleis 1-piperidinyl or hexahydro-1H-azepin-1-yl; R_(8b) is absent; R₁, R₃,R₅, R₆, R₇, and R_(8a) are hydrogen.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is a single bond; X₁ is CR₁; X₂ is CR₂; X₄ isCR₄; X₃ and X₅ are N; Z₁ is O; Z₂ is NH; Ar₁ is 1H-indenyl optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylthio, alkynyl, carboxy, cyano, haloalkoxy, haloalkyl,haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, or nitro;R_(8b) is absent; and R₁, R₂, R₄, R₅, R₆, R₇, and R_(8a) are as definedin formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is a single bond; X₁ is CR₁; X₂ is CR₂; X₄ isCR₄; X₃ and X₅ are N; Z₁ is O; Z₂ is NH; Ar₁ is 1H-indenyl optionallysubstituted with 1 or 2 substituents independently selected from alkyl,haloalkyl, halogen, or heterocycle wherein the heterocycle is1-piperidinyl or hexahydro-1H-azepin-1-yl; R_(8b) is absent; and R₁, R₂,R₄, R₅, R₆, R₇, and R_(8a) are as defined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is a single bond; X₁ is CR₁; X₂ is CR₂; X₄ isCR₄; X₃ and X₅ are N; Z₁ is O; Z₂ is NH; Ar₁ is 1H-indenyl optionallysubstituted with 1 or 2 substituents independently selected from alkyl,haloalkyl, halogen, or heterocycle wherein the heterocycle is1-piperidinyl or hexahydro-1H-azepin-1-yl; R_(8b) is absent; R₁, R₄, R₅,R₆, R₇, and R_(8a) are hydrogen; and R₂ is hydrogen or alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is a single bond; X₁ is CR₁; X₂ is CR₂; X₄ isCR₄; X₃ and X₅ are N; Z₁ is O; Z₂ is NH; Ar₁ is 1H-inden-2-ylsubstituted with 1 or 2 substituents independently selected from alkyl,haloalkyl, halogen, or heterocycle wherein the heterocycle is1-piperidinyl or hexahydro-1H-azepin-1-yl; R₁, R₄, R₅, R₆, R₇, andR_(8a) are hydrogen; R₂ is hydrogen or alkyl; and R_(8b) is absent.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is a single bond; X₁ is CR₁; X₂ is CR₂; X₄ isCR₄; X₃ and X₅ are N; Z₁ is O; Z₂ is NH; Ar₁ is 1H-inden-3-ylsubstituted with 1 or 2 substituents independently selected from alkyl,haloalkyl, halogen, or heterocycle wherein the heterocycle is1-piperidinyl or hexahydro-1H-azepin-1-yl; R₁, R₄, R₅, R₆, R₇, andR_(8a) are hydrogen; R₂ is hydrogen or alkyl; and R_(8b) is absent.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; X₅ is N; Z₁ is O; Z₂ is NH; Ar₁ is 1H-indenyl optionallysubstituted with 1 or 2 substituents independently selected from alkyl,haloalkyl, halogen, or heterocycle wherein the heterocycle is1-piperidinyl or hexahydro-1H-azepin-1-yl; R_(8b) is absent; and R₁, R₃,R₅, R₆, R₇, and R_(8a) are as defined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; X₅ is N; Z₁ is O; Z₂ is NH; Ar₁ is 1H-inden-2-yl optionallysubstituted with 1 or 2 substituents independently selected from alkyl,haloalkyl, halogen, or heterocycle wherein the heterocycle is1-piperidinyl or hexahydro-1H-azepin-1-yl; R_(8b) is absent; R₁, R₃, R₅,R₆, R₇, and R_(8a) are hydrogen.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; X₅ is N; Z₁ is O; Z₂ is NH; Ar₁ is 1H-inden-3-yl optionallysubstituted with 1 or 2 substituents independently selected from alkyl,haloalkyl, halogen, or heterocycle wherein the heterocycle is1-piperidinyl or hexahydro-1H-azepin-1-yl; R_(8b) is absent; R₁, R₃, R₅,R₆, R₇, and R_(8a) are hydrogen.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is a single bond; X₁ is CR₁; X₂ is CR₂; X₄ isCR₄; X₃ and X₅ are N; Z₁ is O; Z₂ is NH; Ar₁ is tetrahydronaphthalenyloptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylthio, alkynyl, carboxy, cyano, haloalkoxy,haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, ornitro; R_(8b) is absent; and R₁, R₂, R₄, R₅, R₆, R₇, and R_(8a) are asdefined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is a single bond; X₁ is CR₁; X₂ is CR₂; X₄ isCR₄; X₃ and X₅ are N; Z₁ is O; Z₂ is NH; Ar₁ is tetrahydronaphthalenyloptionally substituted with 1 or 2 substituents independently selectedfrom alkyl, haloalkyl, halogen, or heterocycle wherein the heterocycleis 1-piperidinyl or hexahydro-1H-azepin-1-yl; R_(8b) is absent; and R₁,R₂, R₄, R₅, R₆, R₇, and R_(8a) are as defined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is a single bond; X₁ is CR₁; X₂ is CR₂; X₄ isCR₄; X₃ and X₅ are N; Z₁ is O; Z₂ is NH; Ar₁ is tetrahydronaphthalenyloptionally substituted with 1 or 2 substituents independently selectedfrom alkyl, haloalkyl, halogen, or heterocycle wherein the heterocycleis 1-piperidinyl or hexahydro-1H-azepin-1-yl; R_(8b) is absent; R₁, R₄,R₅, R₆, R₇, and R_(8a) are hydrogen; and R₂ is hydrogen or alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is a single bond; X₁ is CR₁; X₂ is CR₂; X₄ isCR₄; X₃ and X₅ are N; Z₁ is O; Z₂ is NH; Ar₁ is1,2,3,4-tetrahydronaphthalen-1-yl substituted with 1 or 2 substituentsindependently selected from alkyl, haloalkyl, halogen, or heterocyclewherein the heterocycle is 1-piperidinyl or hexahydro-1H-azepin-1-yl;R₁, R₄, R₅, R₆, R₇, and R_(8a) are hydrogen; R₂ is hydrogen or alkyl;and R_(8b) is absent.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is a single bond; X₁ is CR₁; X₂ is CR₂; X₄ isCR₄; X₃ and X₅ are N; Z₁ is O; Z₂ is NH; Ar₁ is1,2,3,4-tetrahydronaphthalen-2-yl substituted with 1 or 2 substituentsindependently selected from alkyl, haloalkyl, halogen, or heterocyclewherein the heterocycle is 1-piperidinyl or hexahydro-1H-azepin-1-yl;R₁, R₄, R₅, R₆, R₇, and R_(8a) are hydrogen; R₂ is hydrogen or alkyl;and R_(8b) is absent.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; X₅ is N; Z₁ is O; Z₂ is NH; Ar₁ is tetrahydronaphthalenyloptionally substituted with 1 or 2 substituents independently selectedfrom alkyl, haloalkyl, halogen, or heterocycle wherein the heterocycleis 1-piperidinyl or hexahydro-1H-azepin-1-yl; R_(8b) is absent; and R₁,R₃, R₅, R₆, R₇, and R_(8a) are as defined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; Xs is N; Z₁ is O; Z₂ is NH; Ar₁ is1,2,3,4-tetrahydronaphthalen-1-yl optionally substituted with 1 or 2substituents independently selected from alkyl, haloalkyl, halogen, orheterocycle wherein the heterocycle is 1-piperidinyl orhexahydro-1H-azepin-1-yl; R_(8b) is absent; R₁, R₃, R₅, R₆, R₇, andR_(8a) are hydrogen.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; X₅ is N; Z₁ is O; Z₂ is NH; Ar₁ is1,2,3,4-tetrahydronaphthalen-2-yl optionally substituted with 1 or 2substituents independently selected from alkyl, haloalkyl, halogen, orheterocycle wherein the heterocycle is 1-piperidinyl orhexahydro-1H-azepin-1-yl; R_(8b) is absent; R₁, R₃, R₅, R₆, R₇, andR_(8a) are hydrogen.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is a single bond; X₁ is CR₁; X₂ is CR₂; X₄ isCR₄; X₃ and X₅ are N; Z₁ is O; Z₂ is NH; Ar₁ is dihydronaphthalenyloptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylthio, alkynyl, carboxy, cyano, haloalkoxy,haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, ornitro; R_(8b) is absent; and R₁, R₂, R₄, R₅, R₆, R₇ and R_(8a) are asdefined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is a single bond; X₁ is CR₁; X₂ is CR₂; X₄ isCR₄; X₃ and X₅ are N; Z₁ is O; Z₂ is NH; Ar₁ is dihydronaphthalenyloptionally substituted with 1 or 2 substituents independently selectedfrom alkyl, haloalkyl, halogen, or heterocycle wherein the heterocycleis 1-piperidinyl or hexahydro-1H-azepin-1-yl; R_(8b) is absent; and R₁,R₂, R₄, R₅, R₆, R₇, and R_(8a) are as defined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is a single bond; X₁ is CR₁; X₂ is CR₂; X₄ isCR₄; X₃ and X₅ are N; Z₁ is O; Z₂ is NH; Ar₁ is dihydronaphthalenyloptionally substituted with 1 or 2 substituents independently selectedfrom alkyl, haloalkyl, halogen, or heterocycle wherein the heterocycleis 1-piperidinyl or hexahydro-1H-azepin-1-yl; R_(8b) is absent; R₁, R₄,R₅, R₆, R₇, and R_(8a) are hydrogen; and R₂ is hydrogen or alkyl.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is a single bond; X₁ is CR₁; X₂ is CR₂; X₄ isCR₄; X₃ and X₅ are N; Z₁ is O; Z₂ is NH; Ar₁ is3,4-dihydronaphthalen-1-yl substituted with 1 or 2 substituentsindependently selected from alkyl, haloalkyl, halogen, or heterocyclewherein the heterocycle is 1-piperidinyl or hexahydro-1H-azepin-1-yl;R₁, R₄, R₅, R₆, R₇, and R_(8a) are hydrogen; R₂ is hydrogen or alkyl;and R_(8b) is absent.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is a single bond; X₁ is CR₁; X₂ is CR₂; X₄ isCR₄; X₃ and X₅ are N; Z₁ is O; Z₂ is NH; Ar₁ is3,4-dihydronaphthalen-2-yl substituted with 1 or 2 substituentsindependently selected from alkyl, haloalkyl, halogen, or heterocyclewherein the heterocycle is 1-piperidinyl or hexahydro-1H-azepin-1-yl;R₁, R₄, R₅, R₆, R₇, and R_(8a) are hydrogen; R₂ is hydrogen or alkyl;and R_(8b) is absent.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is a single bond; X₁ is CR₁; X₂ is CR₂; X₄ isCR₄; X₃ and X₅ are N; Z₁ is O; Z₂ is NH; Ar₁ is1,2-dihydronaphthalen-1-yl substituted with 1 or 2 substituentsindependently selected from alkyl, haloalkyl, halogen, or heterocyclewherein the heterocycle is 1-piperidinyl or hexahydro-1H-azepin-1-yl;R₁, R₄, R₅, R₆, R₇, and R_(8a) are hydrogen; R₂ is hydrogen or alkyl;and R_(8b) is absent.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is a single bond; X₁ is CR₁; X₂ is CR₂; X₄ isCR₄; X₃ and X₅ are N; Z₁ is O; Z₂ is NH; Ar₁ is1,2-dihydronaphthalen-2-yl substituted with 1 or 2 substituentsindependently selected from alkyl, haloalkyl, halogen, or heterocyclewherein the heterocycle is 1-piperidinyl or hexahydro-1H-azepin-1-yl;R₁, R₄, R₅, R₆, R₇, and R_(8a) are hydrogen; R₂ is hydrogen or alkyl;and R_(8b) is absent.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; X₅ is N; Z₁ is O; Z₂ is NH; Ar₁ is dihydronaphthalenyloptionally substituted with 1 or 2 substituents independently selectedfrom alkyl, haloalkyl, halogen, or heterocycle wherein the heterocycleis 1-piperidinyl or hexahydro-1H-azepin-1-yl; R_(8b) is absent; and R₁,R₃, R₅, R₆, R₇, and R_(8a) are as defined in formula (I).

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; X₅ is N; Z₁ is O; Z₂ is NH; Ar₁ is 3,4-dihydronaphthalen-1-yloptionally substituted with 1 or 2 substituents independently selectedfrom alkyl, haloalkyl, halogen, or heterocycle wherein the heterocycleis 1-piperidinyl or hexahydro-1H-azepin-1-yl; R_(8b) is absent; R₁, R₃,R₅, R₆, R₇, and R_(8a) are hydrogen.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; X₅ is N; Z₁ is O; Z₂ is NH; Ar₁ is 3,4-dihydronaphthalen-2-yloptionally substituted with 1 or 2 substituents independently selectedfrom alkyl, haloalkyl, halogen, or heterocycle wherein the heterocycleis 1-piperidinyl or hexahydro-1H-azepin-1-yl; R_(8b) is absent; R₁, R₃,R₅, R₆, R₇, and R_(8a) are hydrogen.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; X₅ is N; Z₁ is O; Z₂ is NH; Ar₁ is 1,2-dihydronaphthalen-1-yloptionally substituted with 1 or 2 substituents independently selectedfrom alkyl, haloalkyl, halogen, or heterocycle wherein the heterocycleis 1-piperidinyl or hexahydro-1H-azepin-1-yl; R_(8b) is absent; R₁, R₃,R₅, R₆, R₇, and R_(8a) are hydrogen.

In another embodiment of the present invention, compounds of formula (I)are disclosed wherein --- is absent; X₁ is CR₁; X₂ is N; X₃ is NR₃; X₄is a bond; X₅ is N; Z₁ is O; Z₂ is NH; Ar₁ is 1,2-dihydronaphthalen-2-yloptionally substituted with 1 or 2 substituents independently selectedfrom alkyl, haloalkyl, halogen, or heterocycle wherein the heterocycleis 1-piperidinyl or hexahydro-1H-azepin-1-yl; R_(8b) is absent; R₁, R₃,R₅, R₆, R₇, and R_(8a) are hydrogen.

Another embodiment of the present invention relates to pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt or prodrug thereof.

Another embodiment of the present invention relates to a method fortreating a disorder wherein the disorder is ameliorated by inhibitingvanilloid receptor subtype 1 (VR1) in a mammal comprising administeringa therapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt or prodrug thereof.

Another embodiment of the present invention relates to a method fortreating pain in a mammal comprising administering a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt or prodrug thereof.

Another embodiment of the present invention relates to a method fortreating urinary incontinence in a mammal comprising administering atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt or prodrug thereof.

Another embodiment of the present invention relates to a method fortreating bladder overactivity in a mammal comprising administering atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt or prodrug thereof.

Another embodiment of the present invention relates to a method fortreating inflammatory thermal hyperalgesia in a mammal comprisingadministering a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt or prodrug thereof.

Definition of Terms

As used throughout this specification and the appended claims, thefollowing terms have the following meanings:

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens.Representative examples of alkenyl include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkoxy” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of alkoxyalkoxyinclude, but are not limited to, methoxymethoxy, ethoxymethoxy and2-ethoxyethoxy.

The term “alkoxyalkyl” as used herein, means an alkoxy group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of alkoxyalkyl include, butare not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl,and methoxymethyl.

The term “alkoxycarbonyl” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkoxycarbonylalkyl” as used herein, means an alkoxycarbonylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofalkoxycarbonylalkyl include, but are not limited to,3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and2-tert-butoxycarbonylethyl.

The term “alkyl” as used herein, means a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylcarbonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “alkylcarbonylalkyl” as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofalkylcarbonylalkyl include, but are not limited to, 2-oxopropyl,3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl.

The term “alkylcarbonyloxy” as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an oxygen atom. Representative examples of alkylcarbonyloxyinclude, but are not limited to, acetyloxy, ethylcarbonyloxy, andtert-butylcarbonyloxy.

The term “alkylsulfonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkylsulfonyl include, but are not limited to, methylsulfonyl andethylsulfonyl.

The term “alkylthio” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of alkylthio include, but are not limited,methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl, and hexylsulfanyl.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “Ar₁” as used herein, means an aryl group selected fromdihydro-1H-indenyl, 1H-indenyl, tetrahydronaphthalenyl, ordihydronaphthalenyl. The Ar₁ group is attached to the parent molecularmoiety via any position. Representative examples include, but are notlimited to, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl,2,3-dihydro-1H-inden-4-yl, 2,3-dihydro-1H-inden-5-yl, 1H-inden-1-yl,1H-inden-2-yl, 1H-inden-3-yl, 1H-inden-4-yl, 1H-inden-5-yl,1,2,3,4-tetrahydro-1-naphthalenyl, 1,2,3,4-tetrahydro-2-naphthalenyl,1,2,3,4-tetrahydro-5-naphthalenyl, 1,2,3,4-tetrahydro-6-naphthalenyl,1,2-dihydro-1-naphthalenyl, 1,2-dihydro-2-naphthalenyl,1,2-dihydro-3-naphthalenyl, 1,2-dihydro-4-naphthalenyl,1,2-dihydro-5-naphthalenyl, 1,2-dihydro-6-naphthalenyl,1,2-dihydro-7-naphthalenyl, 1,2-dihydro-8-naphthalenyl,3,4-dihydronaphthalen-1-yl, and 3,4-dihydronaphthalen-2-yl.

The Ar₁ groups of this invention can be substituted with 1, 2, 3, 4 or 5substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy,alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl,alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy,carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, haloalkoxy,haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto,mercaptoalkyl, nitro, (CF₃)₂(HO)C—, —NR_(A)S(O)₂R_(B), —S(O)₂OR_(A),—S(O)₂R_(B), —NZ_(A)Z_(B), (NZ_(A)Z_(B))alkyl, (NZ_(A)Z_(B))carbonyl,(NZ_(A)Z_(B))carbonylalkyl or (NZ_(A)Z_(B))sulfonyl, wherein Z_(A) andZ_(B) are each independently hydrogen, alkyl, alkylcarbonyl, formyl,aryl, or arylalkyl. Representative examples of substituted Ar₁ groupsinclude, but are not limited to, 5-tert-butyl-2,3-dihydro-1H-inden-1-yl,5-tert-butyl-2,3-dihydro-1H-inden-2-yl,5-bromo-2,3-dihydro-1H-inden-1-yl,(3R)-5-tert-butyl-3-methyl-2,3-dihydro-1H-inden-1-yl, and(3S)-5-tert-butyl-3-methyl-2,3-dihydro-1H-inden-1-yl.

The term “aryl” as used herein, means a phenyl group, or a bicyclic or atricyclic fused ring system wherein one or more of the fused rings is aphenyl group. Bicyclic fused ring systems are exemplified by a phenylgroup fused to a cycloalkyl group, as defined herein, or another phenylgroup. Tricyclic fused ring systems are exemplified by a bicyclic fusedring system fused to a cycloalkyl group, as defined herein, or anotherphenyl group. Representative examples of aryl include, but are notlimited to, anthracenyl, azulenyl, fluorenyl, indenyl, naphthyl, phenyland tetrahydronaphthyl.

The aryl groups of this invention can be substituted with 1, 2, 3, 4 or5 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl,alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl,cycloalkyl, cycloalkylalkyl, ethylenedioxy, formyl, formylalkyl,haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl,methylenedioxy, mercapto, mercaptoalkyl, nitro, —NZ_(C)Z_(D),(NZ_(C)Z_(D))alkyl, (NZ_(C)Z_(D))carbonyl, (NZ_(C)Z_(D))carbonylalkyl,(NZ_(C)Z_(D))sulfonyl, —NR_(A)S(O)₂R_(B), —S(O)₂OR_(A) and —S(O)₂R_(A)wherein R_(A) and R_(B) are as defined herein.

The term “arylalkyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of arylalkyl include, but arenot limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and2-naphth-2-ylethyl.

The term “aryloxy” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of aryloxy include, but are not limited to,phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy,and 3,5-dimethoxyphenoxy.

The term “arylthio” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of arylthio include, but are not limited to,phenylsulfanyl, naphth-2-ylsulfanyl, and 5-phenylhexylsulfanyl.

The term “carbonyl” as used herein, means a —C(O)— group.

The term “carboxy” as used herein, means a —CO₂H group.

The term “carboxyalkyl” as used herein, means a carboxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of carboxyalkylinclude, but are not limited to, carboxymethyl, 2-carboxyethyl, and3-carboxypropyl.

The term “cyano” as used herein, means a —CN group.

The term “cyanoalkyl” as used herein, means a cyano group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of cyanoalkyl include, butare not limited to, cyanomethyl, 2-cyanoyethyl, and 3-cyanopropyl.

The term “cycloalkyl” as used herein, means a saturated monocyclic ringsystem containing from 3 to 8 carbon atoms. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and cyclooctyl.

The term “ethylenedioxy” as used herein, means a —O(CH₂)₂O— groupwherein the oxygen atoms of the ethylenedioxy group are attached to theparent molecular moiety through one carbon atom forming a 5 memberedring or the oxygen atoms of the ethylenedioxy group are attached to theparent molecular moiety through two adjacent carbon atoms forming a sixmembered ring.

The term “formyl” as used herein, means a —C(O)H group.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkoxy” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of haloalkoxyinclude, but are not limited to, chloromethoxy, 2-fluoroethoxy,trifluoromethoxy, 2-chloro-3-fluoropentyloxy, and pentafluoroethoxy.

The term “haloalkyl” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “haloalkylthio” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkylthio group, as defined herein. Representative examples ofhaloalkylthio include, but are not limited to, trifluoromethylthio.

The term “heterocycle,” as used herein, refers to a three, four, five,six, seven, or eight membered ring containing one or two heteroatomsindependently selected from the group consisting of nitrogen, oxygen,and sulfur. The three membered ring has zero double bonds. The four andfive membered ring has zero or one double bond. The six membered ringhas zero, one, or two double bonds. The seven and eight membered ringshave zero, one, two, or three double bonds. The heterocycle groups ofthe present invention can be attached to the parent molecular moietythrough a carbon atom or a nitrogen atom. Representative examples ofheterocycle include, but are not limited to, azetidinyl,hexahydro-1H-azepinyl, hexahydroazocin-(2H)-yl, morpholinyl,piperazinyl, piperidinyl, pyrrolidinyl, and thiomorpholinyl.

The heterocycles of the present invention are substituted with 0, 1, 2,3, or 4 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl,alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkynyl, arylalkyl,arylalkoxycarbonyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halo,hydroxy, hydroxyalkyl, mercapto, and nitro.

The term “hydroxy” as used herein, means an —OH group.

The term “hydroxyalkyl” as used herein, means at least one hydroxygroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and2-ethyl-4-hydroxyheptyl.

The term “mercapto” as used herein, means a —SH group.

The term “mercaptoalkyl” as used herein, means a mercapto group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of mercaptoalkylinclude, but are not limited to, 2-mercaptoethyl and 3-mercaptopropyl.

The term “methylenedioxy” as used herein, means a —OCH₂O— group whereinthe oxygen atoms of the methylenedioxy are attached to the parentmolecular moiety through two adjacent carbon atoms.

The term “nitro” as used herein, means a —NO₂ group.

The term “—NZ_(A)Z_(B)” as used herein, means two groups, Z_(A) andZ_(B), which are appended to the parent molecular moiety through anitrogen atom. Z_(A) and Z_(B) are each independently selected fromhydrogen, alkyl, alkylcarbonyl, formyl, aryl and arylalkyl.Representative examples of —NZ_(A)Z_(B) include, but are not limited to,amino, methylamino, acetylamino, benzylamino, phenylamino, andacetylmethylamino.

The term “(NZ_(A)Z_(B))alkyl” as used herein, means a —NZ_(A)Z_(B)group, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples of(NZ_(A)Z_(B))alkyl include, but are not limited to, aminomethyl,2-(methylamino)ethyl, 2-(dimethylamino)ethyl and(ethylmethylamino)methyl.

The term “(NZ_(A)Z_(B))carbonyl” as used herein, means a —NZ_(A)Z_(B)group, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of(NZ_(A)Z_(B))carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl and(ethylmethylamino)carbonyl.

The term “(NZ_(A)Z_(B))carbonylalkyl” as used herein, means a(NZ_(A)Z_(B))carbonyl group, as defined herein, appended to the parentmolecular moiety through an alkyl group, as defined herein.Representative examples of (NZ_(A)Z_(B))carbonylalkyl include, but arenot limited to, (aminocarbonyl)methyl, 2-((methylamino)carbonyl)ethyland ((dimethylamino)carbonyl)methyl.

The term “(NZ_(A)Z_(B))sulfonyl” as used herein, means a —NZ_(A)Z_(B)group, as defined herein, appended to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples of(NZ_(A)Z_(B))sulfonyl include, but are not limited to, aminosulfonyl,(methylamino)sulfonyl, (dimethylamino)sulfonyl and(ethylmethylamino)sulfonyl.

The term “—NZ_(C)Z_(D)” as used herein, means two groups, Z_(C) andZ_(D), which are appended to the parent molecular moiety through anitrogen atom. Z_(C) and Z_(D) are each independently selected fromhydrogen, alkyl, alkylcarbonyl, formyl, aryl and arylalkyl.Representative examples of —NZ_(C)Z_(D) include, but are not limited to,amino, methylamino, acetylamino, benzylamino, phenylamino, andacetylmethylamino.

The term “(NZ_(C)Z_(D))alkyl” as used herein, means a —NZ_(C)Z_(D)group, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples of(NZ_(C)Z_(D))alkyl include, but are not limited to, aminomethyl,2-(methylamino)ethyl, 2-(dimethylamino)ethyl and(ethylmethylamino)methyl.

The term “(NZ_(C)Z_(D))carbonyl” as used herein, means a —NZ_(C)Z_(D)group, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of(NZ_(C)Z_(D))carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl and(ethylmethylamino)carbonyl.

The term “(NZ_(C)Z_(D))carbonylalkyl” as used herein, means a(NZ_(C)Z_(D))carbonyl group, as defined herein, appended to the parentmolecular moiety through an alkyl group, as defined herein.Representative examples of (NZ_(C)Z_(D))carbonylalkyl include, but arenot limited to, (aminocarbonyl)methyl, 2-((methylamino)carbonyl)ethyland ((dimethylamino)carbonyl)methyl.

The term “(NZ_(C)Z_(D))sulfonyl” as used herein, means a —NZ_(C)Z_(D)group, as defined herein, appended to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples of(NZ_(C)Z_(D))sulfonyl include, but are not limited to, aminosulfonyl,(methylamino)sulfonyl, (dimethylamino)sulfonyl and(ethylmethylamino)sulfonyl.

The term “oxo” as used herein, means ═O.

The term “sulfonyl” as used herein, means a —S(O)₂— group.

Preferred compounds of the present invention include, but are notlimited to,

-   N-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-5-isoquinolinylurea;-   N-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-(3-methyl-5-isoquinolinyl)urea;-   (+)N-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-(3-methyl-5-isoquinolinyl)urea;-   (−)    N-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-(3-methyl-5-isoquinolinyl)urea;-   (−)    N-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-5-isoquinolinylurea;-   (+)    N-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-5-isoquinolinylurea;-   N-(5-bromo-2,3-dihydro-1H-inden-1-yl)-N′-5-isoquinolinylurea;-   methyl    4-({[(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylate;-   N-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-1H-indazol-4-ylurea;-   methyl    4-[({[(1S)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;-   methyl    4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;-   N-[(1S)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-1H-indazol-4-ylurea;-   N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-1H-indazol-4-ylurea;-   methyl    4-[({[5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate;-   N-1H-indazol-4-yl-N′-[5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]urea;-   methyl 4-({[(5-piperidin-1-yl-2,3-dihydro-    1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylate;-   N-1H-indazol-4-yl-N′-(5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl)urea;-   methyl    4-({[(5-hexahydro-1H-azepin-1-yl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylate;-   N-(5-hexahydro-1H-azepin-1-yl-2,3-dihydro-1H-inden-1-yl)-N′-1H-indazol-4-ylurea;-   N-1H-indazol-4-yl-N′-[(1R)-5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl]urea;-   N-1H-indazol-4-yl-N′-[(1S)-5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl]urea;-   isopropyl    4-({[(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylate;-   isobutyl    4-({[(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylate;    or a pharmaceutically acceptable salt or prodrug thereof.

Compounds of the present invention can exist as stereoisomers, whereinasymmetric or chiral centers are present. Stereoisomers are designated(R) or (S), depending on the configuration of substituents around thechiral carbon atom. The terms (R) and (S) used herein are configurationsas defined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., (1976), 45: 13-30. The presentinvention contemplates various stereoisomers and mixtures thereof andare specifically included within the scope of this invention.Stereoisomers include enantiomers, diastereomers, and mixtures ofenantiomers or diastereomers. Individual stereoisomers of compounds ofthe present invention may be prepared synthetically from commerciallyavailable starting materials which contain asymmetric or chiral centersor by preparation of racemic mixtures followed by resolution, atechnique well-known to those of ordinary skill in the art. Thesemethods of resolution are exemplified by (1) attachment of a mixture ofenantiomers to a chiral auxiliary, separation of the resulting mixtureof diastereomers by recrystallization or chromatography and liberationof the optically pure product from the auxiliary, (2) direct separationof the mixture of optical enantiomers on chiral chromatographic columns,or (3) formation of a diastereomeric salt followed by selectiverecrystallization of one of the diastereomeric salts.

Compounds of the present invention were named by ACD/ChemSketch version5.0 (developed by Advanced Chemistry Development, Inc., Toronto, ON,Canada) or were given names which appeared to be consistent with ACDnomenclature.

Abbreviations

Abbreviations which have been used in the descriptions of the Schemesand the Examples that follow are: atm for atmosphere(s); DBU for1,8-diazabicyclo[5.4.0]undec-7-ene; DCC for1,3-dicyclohexylcarbodiimide; DMAP for 4-dimethylaminopyridine; DMF forN,N-dimethylformamide; DMSO for dimethylsulfoxide; EDCI or EDC for1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride; Et forCH₃CH₂; HPLC high pressure liquid chromatography; Me for CH₃; Ph forphenyl; psi for pounds per square inch; and THF for tetrahydrofuran.

Preparation of Compounds of the Present Invention

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic Schemes andExamples which illustrate a means by which the compounds of the presentinvention can be prepared.

Ureas of general formula (4), wherein R₁, R₂, R₄, R₅, R₆, R₇, and Ar₁are as defined in formula (I), may be prepared as described in Scheme 1.5-Aminoisoquinolines of general formula (1), purchased commercially orprepared using standard chemistry known to those in the art, can betreated with trichloroacetyl chloride and a base such as, but notlimited to, triethylamine in a solvent such as dichloromethane toprovide trichloroacetamides of general formula (2). Trichloroacetamidesof general formula (2) can be treated with amines of general formula (3)and a non-nucleophilic base such as, but not limited to, DBU in asolvent such as, but not limited to, acetonitrile to provide ureas ofgeneral formula (4).

Carbamates of general formula (6), wherein R₁, R₂, R₄, R₅, R₆, R₇, andAr₁ are as defined in formula (I), may also be prepared as described inScheme 1. Trichloroacetamides of general formula (2) can be treated withalcohols of general formula (5) and a non-nucleophilic base such as, butnot limited to, DBU in a solvent such as, but not limited to,acetonitrile to provide carbamates of general formula (6).

Ureas of general formula (4), wherein R₁, R₂, R₄, R₅, R₆, R₇, and Ar₁are as defined in formula (I), may be prepared as described in Scheme 2.Amines of general formula (3) can be treated with phosgene ortriphosgene and DMAP in a solvent such as, but not limited to,dichloromethane to provide isocyanates of general formula (8).5-Aminoisoquinolines of general formula (1) can be treated withisocyanates of general formula (8) in a solvent such as, but not limitedto, toluene or THF or a combination thereof to provide ureas of generalformula (4).

Ureas of general formula (4), wherein R₁, R₂, R₄, R₅, R₆, R₇, and Ar₁are as defined in formula (I), may be prepared as described in Scheme 3.5-Aminoisoquinolines of general formula (1) can be treated with phosgeneor triphosgene and DMAP in a solvent such as, but not limited to,dichloromethane to provide isocyanates of general formula (10).Isocyanates of general formula (10) can be treated with amines ofgeneral formula (3) in a solvent such as, but not limited to, toluene orTHF or a combination thereof to provide ureas of general formula (4).

Ureas of general formula (20), wherein R₁, R₂, R₃, R₅, R₆, R₇, and Ar₁are as defined in formula (I), and carbamates of general formula (21),wherein R₁, R₂, R₃, R₅, R₆, R₇, and Ar₁ are as defined in formula (I),may be prepared as described in Scheme 4. 4-Aminoindoles of generalformula (19), purchased commercially or prepared using standardchemistry known to those in the art, may be processed as described inSchemes 1-3 to provide ureas of general formula (20) and carbamates ofgeneral formula (21).

Ureas of general formula (23), wherein R₁, R₃, R₅, R₆, R₇, and Ar₁ areas defined in formula (I), and carbamates of general formula (24),wherein R₁, R₃, R₅, R₆, R₇, and Ar₁ are as defined in formula (I), maybe prepared as described in Scheme 4. 4-Aminoindazoles of generalformula (22), purchased commercially or prepared using standardchemistry known to those in the art, may be processed as described inSchemes 1-3 to provide ureas of general formula (23) and carbamates ofgeneral formula (24).

Amides of general formula (32), wherein R₁, R₂, R₄, R₅, R₆, R₇, and Ar₁are as defined in formula (I), can be prepared as described in Scheme 5.Amines of general formula (1) can be treated with an acid such as, butnot limited to, concentrated sulfuric acid and N-bromosuccinimide (NBS)to provide bromides of general formula (27). Bromides of general formula(27) can be treated with an organolithium reagent such as, but notlimited to, n-butyllithium and diethyl oxalate in a solvent such as, butnot limited to, THF to provide keto esters of general formula (28). Ketoesters of general formula (28) can be treated with a reducing agent suchas, but not limited to, 10% Pd/C under a hydrogen atmosphere (50 psi) ina solvent such as, but not limited to, ethanol to provide hydroxy estersof general formula (29). Hydroxy esters of general formula (29) can betreated with an acid chloride such as, but not limited to, acetylchloride in a solvent such as, but not limited to, pyridine to providediesters of general formula (30). Diesters of general formula (30) canbe treated with 10% Pd/C and a base such as, but not limited to,triethylamine under a hydrogen atmosphere (60 psi) in a solvent such as,but not limited to, ethanol to provide esters of general formula (31).Esters of general formula (31) can be treated with amines of generalformula (3) to provide amides of general formula (32). Alternatively,esters of general formula (31) can be treated with aqueous base such as,but not limited to, aqueous sodium hydroxide or aqueous potassiumhydroxide to provide the acids which can then be converted into amidesof general formula (32) by treatment with amines of general formula (3)under standard DCC or EDCI coupling procedures that are well known inthe art.

Esters of general formula (33), wherein R₁, R₂, R₄, R, R₆, R₇, and Ar₁are as defined in formula (I), can be prepared as described in Scheme 5.Esters of general formula (31) can be treated with alcohols of generalformula (5) under standard transesterification conditions well known tothose of skill in the art to provide esters of general formula (33).

Ureas of general formula (39) and ureas of general formula (40), whereinR₅, R₆, R₇, and Ar, are as defined in formula (I) and R is alkyl asdefined herein, can be prepared as described in Scheme 6. Nitro anilinesof general formula (35) can be treated with sodium nitrite and an acidincluding, but not limited to, acetic acid in water to provide indazolesof general formula (36). Indazoles of general formula (36) can betreated with chloroformates to provide indazoles of general formula(37). Indazoles of general formula (37) can be treated with a transitionmetal catalyst including, but not limited to, palladium on carbon undera hydrogen atmosphere (about 1 atm to about 60 atm) to provide indazolesof general formula (38). Indazoles of general formula (38) can beprocessed as described in Scheme 1-3 to provide indazoles of generalformula (39). Indazoles of general formula (39) can be treated with abase including, but not limited to, sodium hydroxide or potassiumhydroxide to provide indazoles of general formula (40).

2,3-Dihydro-1H-inden-1-ylamines of general formula (44), wherein R is 1,2, 3, 4, or 5 substituents independently selected from alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl,carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl,haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl,mercapto, mercaptoalkyl, nitro, (CF₃)₂(HO)C—, —NR_(A)S(O)₂R_(B),—S(O)₂OR_(A), —S(O)₂R_(B), —NZ_(A)Z_(B), (NZ_(A)Z_(B))alkyl,(NZ_(A)Z_(B))carbonyl, (NZ_(A)Z_(B))carbonylalkyl or(NZ_(A)Z_(B))sulfonyl, wherein Z_(A) and Z_(B) are each independentlyhydrogen, alkyl, alkylcarbonyl, formyl, aryl, or arylalkyl, can beprepared as described in Scheme 7. Indan-1-ones of general formula (42)can be treated with hydroxylamines including, but not limited to,O-methylhydroxylamine to provide oximes of general formula (43). Oximesof general formula (43) can be treated with palladium on carbon under ahydrogen atmosphere (about 1 atm to about 60 atm) to provide2,3-dihydro-1H-inden-1-ylamines of general formula (44).

The following Examples are intended as an illustration of and not alimitation upon the scope of the invention as defined in the appendedclaims.

EXAMPLE 1N-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-5-isoquinolinylureaExample 1A 1-(4-tert-butylphenyl)-3-chloro-1-propanone

A solution of tert-butyl benzene (31 ml, 200 mmol) and3-chloro-propionyl chloride (19 ml, 200 mmol) in methylene chloride (75ml) was added dropwise to a suspension of aluminum chloride (29.33 g,220 mmol) in methylene chloride (300 ml) at 0° C. The reaction mixturewas allowed to warm to ambient temperature, stirred for 16 hours, andquenched with water dropwise. The reaction mixture was washed withwater, dried with magnesium sulfate, and the filtrate was evaporatedunder reduced pressure to provide the title compound which was usedwithout further purification in the next step.

Example 1B 5-tert-butyl-1-indanone

1-(4-tert-Butylphenyl)-3-chloro-1-propanone (22.25 g, 99 mmol) wasdissolved in concentrated sulfuric acid (100 ml) and heated on a waterbath at 95° C. for 2.5 hours. The reaction mixture was cooled, pouredonto ice, and extracted with diethyl ether. The combined organicextracts were washed with saturated aqueous sodium bicarbonate, driedwith magnesium sulfate, and the filtrate was evaporated under reducedpressure to provide the title compound which was used without furtherpurification in the next step.

Example 1C 5-tert-butyl-1-indanone O-methyloxime

5-tert-Butyl-1-indanone (13.41 g, 71.23 mmol) and methoxyaminehydrochloride (6.68 g, 80 mmol) were disolved in pyridine (75 ml) andstirred at ambient temperature for 16 hours. The mixture was evaporatedunder reduced pressure and the residue was partitioned between water anddiethyl ether (X2). The combined organic layers were washed with 1Naqueous hydrochloric acid, dried with magnesium sulfate, and thefiltrate was evaporated under reduced pressure to provide the titlecompound which was used without further purification in the next step.

Example 1D 5-tert-butyl-2,3-dihydro-1H-inden-1-ylamine

5-tert-Butyl-1-indanone O-methyloxime (4.37 g, 20.2 mmol) and 10%palladium on carbon (2.2 g) were combined in methanol (50 ml) andammonia (10 ml) and placed in a Parr apparatus which was charged withhydrogen to 60 psi. The reaction was shaken at 50° C. for 16 hours. Thereaction mixture was filtered and the filtrate was evaporated underreduced pressure. The residue was treated with diethyl ether (100 ml)and extracted with hydrochloric acid (1N, 3×50 ml). The combined aqueousextracts were neutralized with sodium hydroxide (6 g) in water (25 ml)and extracted with diethyl ether. The organic extracts were combined,dried with magnesium sulfate, and the filtrate was evaporated underreduced pressure to provide the title compound which was used withoutfurther purification in the next step.

Example 1E 5-isocyanatoisoquinoline

Phosgene (20 ml, 20% in toluene from Fluka) in CH₂Cl₂ (300 mL) at 0° C.was treated with DMAP (10 g) in CH₂Cl₂ (100 mL) slowly. After completeaddition, the mixture was treated with 5-aminoisoquinoline (5 g) inCH₂Cl₂ (100 mL) dropwise. The mixture was allowed to warm to roomtemperature and then stirred overnight. The solvent was removed underreduced pressure. The solid residue was extracted with diethyl ether(400 mL). The diethyl ether was filtered to provide the title compoundin diethyl ether as a pale yellow solution. The diethyl ether solutionwas used in subsequent reactions without further purification.

Example 1FN-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-5-isoquinolinylurea

5-tert-Butyl-2,3-dihydro-1H-inden-1-ylamine (150 mg, 1.13 mmol) indiethyl ether (10 mL) was treated with 5-isocyanatoisoquinoline indiethyl ether. The mixture was stirred for 2 hours, filtered, and thefilter cake was washed with diethyl ether to provide the title compound.NMR (DMSO-d₆) 1.29 (s, 9H), 1.78-1.90 (m, 1H), 2.43-2.54 (m, 1H, buriedunder DMSO), 2.76-3.05 (m, 2H), 5.19 (m, 1H), 7.27 (m, 2H), 7.31 (m,1H), 7.43 (d, 1H), 7.89 (t, 1H), 8.05 (d, 1H), 8.63 (d, 1H), 8.69 (d,1H), 9.33 (s, 1H), 9.73 (s, 1H); MS (ESI+) 360 (M+H)⁺; Elemental:Calculated for C₂₃H₂₅N₃O.HCl.0.5H₂O: C, 68.22; H, 6.72; N, 10.38; Found:C, 68.31; H, 6.81; N, 10.16.

EXAMPLE 2N-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-(3-methyl-5-isoquinolinyl)ureaExample 2A 5-isocyanato-3-methylisoquinoline

The title compound was prepared using the procedure described in Example1E using 3-methyl-5-isoquinolinamine instead of 5-aminoisoquinoline.

Example 2BN-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-(3-methyl-5-isoquinolinyl)urea

The title compound was prepared using the procedure described in Example1F using 5-isocyanato-3-methylisoquinoline instead of5-isocyanatoisoquinoline. NMR (DMSO-d₆) 1.29 (s, 9H), 1.78-1.91 (m, 1H),2.43-2.53 (m, 1H, buried under DMSO), 2.75 (s, 3H), 2.79-2.87 (m, 1H),2.91-3.02 (m, 1H), 5.19 (m, 1H), 7.29 (m, 4H), 7.80 (t, 1H), 7.97 (d,1H), 8.40 (s, 1H), 8.61 (d, 1H), 9.13 (s, 1H), 9.64 (s, 1H); MS (ESI+)374 (M+H)⁺; Elemental: Calculated for C₂₄H₂₇N₃O.HCl.0.8H₂O: C, 67.93; H,7.03; N, 9.90; Found: C, 67.85; H, 7.06; N, 9.66.

EXAMPLE 3 (+)N-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-(3-methyl-5-isoquinolinyl)urea

RacemicN-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-(3-methyl-5-isoquinolinyl)ureawas resolved by chiral HPLC using a Chiralcel OD, 20 micron, 5 cm ID×25cm column with a mobile phase of hexanes (with 0.1% DEA)/ethanol at a90/10 to 92/8 ratio. The flow rate was 50 ml/min and the sample loadingwas 100-200 mg per run. [α]_(D) +14.4° (c 1.0; MeOH); NMR (DMSO-d₆) 1.29(s, 9H), 1.78-1.91 (m, 1H), 2.43-2.53 (m, 1H, buried under DMSO), 2.75(s, 3H), 2.79-2.87 (m, 1H), 2.91-3.02 (m, 1H), 5.19 (m, 1H), 7.29 (m,4H), 7.80 (t, 1H), 7.97 (d, 1H), 8.40 (s, 1H), 8.61 (d, 1H), 9.13 (s,1H), 9.64 (s, 1H); MS (ESI+) 374 (M+H)⁺; Elemental: Calculated forC₂₄H₂₇N₃O.HCl.0.9H₂O: C, 67.64; H, 7.05; N, 9.86; Found: C, 67.77; H,7.12; N, 9.77.

EXAMPLE 4 (−)N-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-(3-methyl-5-isoquinolinyl)urea

The title compound was obtained using chiral HPLC as described inExample 3. [α]_(D) −15.3° (c 0.89; MeOH); NMR (DMSO-d₆) 1.29 (s, 9H),1.78-1.91 (m, 1H), 2.43-2.53 (m, 1H, buried under DMSO), 2.75 (s, 3H),2.79-2.87 (m, 1H), 2.91-3.02 (m, 1H), 5.19 (m, 1H), 7.29 (m, 4H), 7.80(t, 1H), 7.97 (d, 1H), 8.40 (s, 1H), 8.61 (d, 1H), 9.13 (s, 1H), 9.64(s, 1H); MS (ESI+) 374 (M+H)⁺; Elemental: Calculated forC₂₄H₂₇N₃O.HCl.H₂O: C, 67.36; H, 7.07; N, 9.82; Found: C, 67.29; H, 7.20;N, 9.91.

EXAMPLE 5 (−)N-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-5-isoquinolinylurea

RacemicN-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-5-isoquinolinylurea wasresolved by chiral HPLC using a Chiralcel OD, 20 micron, 5 cm ID×25 cmcolumn with a mobile phase of hexanes (with 0.1% DEA)/ethanol at a 90/10to 92/8 ratio, the flow rate was 50 ml/minutes. [α]_(D) −29.4° (c 0.89;MeOH); NMR (DMSO-d₆) 1.06 (t, 0.3H (EtOH)), 1.29 (s, 9H), 1.78-1.90 (m,1H), 2.43-2.54 (m, 1H, buried under DMSO), 2.76-3.05 (m, 2H), 3.44 (q,0.2H (EtOH)), 5.19 (m, 1H), 7.27 (m, 2H), 7.31 (m, 1H), 7.43 (d, 1H),7.89 (t, 1H), 8.05 (d, 1H), 8.63 (d, 1H), 8.69 (d, 1H), 9.33 (s, 1H),9.73 (s, 1H); MS (ESI+) 360 (M+H)⁺; Elemental: Calculated forC₂₃H₂₅N₃O.HCl.0.4H₂O.0.1EtOH: C, 68.34; H, 6.77; N, 10.31; Found: C,68.44; H, 6.77; N, 10.30.

EXAMPLE 6 (+)N-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-5-isoquinolinylurea

RacemicN-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-5-isoquinolinylurea wasresolved by chiral HPLC using a Chiralcel OD, 20 micron, 5 cm ID×25 cmcolumn with a mobile phase of hexanes (with 0.1% DEA)/ethanol at a 90/10to 92/8 ratio, the flow rate was 50 ml/minutes. [α]_(D) +33.3° (c 0.84;MeOH); NMR (DMSO-d₆) 1.06 (t, 0.6H (EtOH)), 1.29 (s, 9H), 1.78-1.90 (m,1H), 2.43-2.54 (m, 1H, buried under DMSO), 2.76-3.05 (m, 2H), 3.44 (q,0.4H (EtOH)), 5.19 (m, 1H), 7.27 (m, 2H), 7.31 (m, 1H), 7.43 (d, 1H),7.89 (t, 1H), 8.05 (d, 1H), 8.63 (d, 1H), 8.69 (d, 1H), 9.33 (s, 1H),9.73 (s, 1H); MS (ESI+) 360 (M+H)⁺; Elemental: Calculated forC₂₃H₂₅N₃O.HCl.0.2H₂O.0.2EtOH: C, 68.76; H, 6.81; N, 10.28; Found: C,68.69; H, 6.83; N, 10.27.

EXAMPLE 7 N-(5-bromo-2,3-dihydro-1H-inden-1-yl)-N′-5-isoquinolinylureaExample 7A 5-bromo-1-indanone O-methyloxime

5-Bromo-1-indanone and O-methylhydroxylamine hydrochloride were combinedin pyridine and stirred at ambient temperature for 16 hours. The mixturewas concentrated under reduced pressure and the residue was suspended indiethyl ether. The suspension was filtered and the filter cake waswashed with diethyl ether. The filtrate was washed with water, 1N HCl,water, and concentrated to provide the title compound. ¹H NMR (300 MHz,d₆-DMSO) 7.63 (m, 2H), 7.48 (m, 2H), 3.90 (s, 3H), 3.00 (m, 2H), 2.80(m, 2H); MS (DCI/NH₃) m/e 240 (M+H)⁺.

Example 7B 5-bromo-1-indanamine

The title compound was prepared using 5-bromo-1-indanone O-methyloximeand the procedure described in Synthesis, 995-996 (1988).

Example 7C N-(5-bromo-2,3-dihydro-1H-inden-1-yl)-N′-5-isoquinolinylurea

The title compound was prepared using the procedure described in Example1F using 5-bromo-1-indanamine instead of5-tert-butyl-2,3-dihydro-1H-inden-1-ylamine. ¹H NMR (300 MHz, d₆-DMSO)9.80 (s, 1H), 9.52 (s, 1H), 8.72 (m, 3H), 8.08 (d, 1H), 7.90 (t, 1H),7.67 (d, 1H), 7.49 (m, 1H), 7.40 (m, 1H), 7.31 (d, 1H), 5.20 (m, 1H),3.02-2.80 (m, 3H), 1.83 (m, 1H); MS (DCI/NH₃) m/e 382 (M+H)⁺; Anal.Calcd. For C₁₉H₁₆N₃OBr. 1.0 HCl. 1.5H₂O: C, 51.20; H, 4.52; N, 9.43.Found: C, 51.21; H, 4.18; N, 8.90.

EXAMPLE 8 methyl4-({[(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylateExample 8A 4-nitro-1H-indazole

2-Methyl-3-nitroaniline (20 g) in acetic acid (˜200 mL) was treated withNaNO₂ (20 g) in water (50 mL) at 4° C. (mechanical stirring). Thereaction mixture was allowed to warm to room temperature and stirovernight. The solvent was removed under reduced pressure. The residuewas treated with water (700 mL) and the mixture was filtered. The solidwas dried at 45° C. in a vacuum oven overnight to provide the titlecompound. ¹H NMR (DMSO) δ 8.56 (s, 1H), 8.2-8.05 (dd, 2H), 7.6 (t, 1H).

Example 8B methyl 4-nitro-1H-indazole-1-carboxylate

NaH (0.3 g, 12.5 mmol ) in DMF (5 mL) was treated with4-nitro-1H-indazole (1.33 g, 10 mmol) at 0° C. The reaction mixture wasallowed to warm to room temperature and stir for 1 hour. The mixture wastreated with methyl chloroformate (0.9 mL) and stirred at roomtemperature for 3 hours. The mixture was treated with water and filteredto provide the title compound as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ4.1 9 (s, 3H), 7.9 (t, 1H), 8.38 (d, 1H), 8.62 (d, 1H), 8.85 (s, 1H).

Example 8C methyl 4-amino-1H-indazole-1-carboxylate

Methyl 4-nitro-1H-indazole-1-carboxylate 1.66 g, 7.5 mmol) and 10% Pd/Cwere combined in ethanol (20 mL) and exposed to a hydrogen atmosphere.The reaction mixture was heated at 80° C. for 20 minutes, allowed tocool to room temperature, and filtered through Celite. The filtrate wasevaporated to provide title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 6.1(s, 2H), 6.41 (dd, 1H), 7.21 (m, 2H), 8.42 (s, 1H).

Example 8D methyl4-({[(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylate

Methyl 4-amino-1H-indazole-1-carboxylate (4.59 g, 24 mmol) in toluene(800 ml) was treated with phosgene (20% in toluene, 25.4 ml, 48 mmol).The mixture was heated at reflux for 3 hours, cooled, and the solventremoved under vacuum. The residue in diethyl ether (800 ml) and triethylamine (20 ml) was filtered and then treated with5-tert-butyl-2,3-dihydro-1H-inden-1-ylamine (20 mmol, free base preparedfrom 4.52 g of the HCl salt). After stirring at ambient temperature for16 hours, the solvent was removed under vacuum and the residuetriturated with a 1:1 mixture of diethyl ether and hexanes to providethe title compound. ¹H NMR (DMSO-d₆) δ 1.28 (s, 9H), 1.78-1.91 (m, 1H),2.39-2.48 (m, 1H), 2.75-2.88 (m, 1H), 2.91-3.02 (m, 1H), 4.04 (s, 3H),5.17 (m, 1H), 6.73 (d, 1H), 7.27 (s, 2H), 7.30 (m, 1H), 7.50 (m, 1H),7.69 (d, 1H), 7.88 (d, 1H), 8.41 (s, 1H), 8.87 (s, 1H); MS (ESI+): 407(M+H)⁺; Elemental: Calculated for C₂₃H₂₆N₄O₃.0.35Et₂O.0.15toluene: C,68.50; H, 6.93; N, 12.56; Found: C, 68.42; H, 6.66; N, 12.42.

EXAMPLE 9N-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-N′-1H-indazol-4-ylurea

Methyl4-({[(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylate(5.67 g, 14 mmol) in tetrahydrofuran (20 ml) was treated with A 5Msolution of sodium hydroxide in methanol (8 ml, 40 mmol). After stirringfor 30 minutes, the reaction mixture was diluted with water andfiltered. The solid was air-dried and then treated with ethanolic HCl toprovide the title compound as the hydrochloride salt. ¹H NMR (DMSO-d₆) δ1.06 (t, 1.8H, EtOH), 1.27 (s, 9H), 1.75-1.88 (m, 1H), 2.40-2.48 (m,1H), 2.76-2.88 (m, 1H), 2.90-3.01 (m, 1H), 3.44 (q, 1.2H, EtOH), 5.12(m, 1H), 6.84 (br d, 1H), 7.05 (d, 1H), 7.20, (m, 1H), 7.26 (s, 2H),7.31 (s, 1H), 7.69 (d, 1H), 8.10 (s, 1H), 8.70 (s, 1H); MS (ESI+): 349(M+H)⁺; Elemental: Calculated for C₂₁H₂₄N₄O.HCl.0.6EtOH.0.6H₂O: C,62.98; H, 7.09; N, 13.23; Found: C, 63.09; H, 6.97; N, 13.18.

EXAMPLE 10 methyl4-[({[(1S)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]1-H-indazole-1-carboxylateExample 10A (1S)-5-tert-butyl-2,3-dihydro-1H-inden-1-ylamine

5-tert-Butyl-2,3-dihydro-1H-inden-1-ylamine (25.51 g, 93% potency),N-acetyl-(L)-leucine (23.34 g), and methanol (315 mL) were combined andheated at 65° C. for 1 hour. The solution was allowed to cool to ambienttemperature. The solids were filtered and washed with toluene. The solidwas then resuspended in methanol (125 mL) and brought to reflux. Thesolution was allowed to cool to ambient temperature and the solids werefiltered. The solid was dried at 40° C. under reduced pressure toprovide the title compound (98.7% ee).

Example 10B methyl4-[({[(1S)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate

The title compound was prepared using the procedure in Example 8D,except using (1S)-5-tert-butyl-2,3-dihydro-1H-inden-1-ylamine (free baseprepared from the N-acetyl-(L)-Leucine salt), instead of5-tert-butyl-2,3-dihydro-1H-inden-1-ylamine. ¹H NMR (DMSO-d₆) δ 1.28 (s,9H), 1.78-1.91 (m, 1H), 2.39-2.48 (m, 1H), 2.75-2.88 (m, 1H), 2.91-3.02(m, 1H), 4.04 (s, 3H), 5.17 (m, 1H), 6.73 (d, 1H), 7.27 (s, 2H), 7.30(m, 1H), 7.50 (m, 1H), 7.69 (d, 1H), 7.88 (d, 1H), 8.39 (s, 1H), 8.84(s, 1H); MS (ESI+): 407 (M+H)⁺.

EXAMPLE 11 methyl4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylateExample 11A (1S)-5-tert-butyl-2,3-dihydro-1H-inden-1-ylamine

5-tert-Butyl-2,3-dihydro-1H-inden-1-ylamine (11.70 g, 44.4% ee),N-acetyl-(D)-leucine (11.78 g), and methanol (120 mL) were combined andheated at 65° C. for 1 hour. The solution was allowed to cool to ambienttemperature. The solids were filtered and washed with toluene. The solidwas then resuspended in methanol (125 mL) and brought to reflux. Thesolution was allowed to cool to ambient temperature and the solids werefiltered. The solid was dried at 40° C. under reduced pressure toprovide the title compound (98.7% ee).

Example 11B methyl4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate

The title compound was prepared using the procedure in Example 8D,except using (1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-ylamine (free baseprepared from the N-acetyl-(D)-Leucine salt) instead of5-tert-butyl-2,3-dihydro-1H-inden-1-ylamine. ¹H NMR (DMSO-d₆) δ 1.28 (s,9H), 1.78-1.91 (m, 1H), 2.39-2.48 (m, 1H), 2.75-2.88 (m, 1H), 2.91-3.02(m, 1H), 4.04 (s, 3H), 5.17 (m, 1H), 6.73 (d, 1H), 7.27 (s, 2H), 7.30(m, 1H), 7.50 (m, 1H), 7.69 (d, 1H), 7.88 (d, 1H), 8.39 (s, 1H), 8.84(s, 1H); MS (ESI+) 407 (M+H)⁺; Elemental: Calculated for C₂₃H₂₆N₄O₃: C,67.96; H, 6.45; N, 13.78; Found: C, 67.85; H, 6.51; N, 13.56.

EXAMPLE 12N-[(1S)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-1H-indazol-4-ylurea

The title compound was prepared using the procedure in Example 9, exceptusing methyl4-[({[(1S)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylateinstead of methyl4-[({[5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate.¹H NMR (DMSO-d) δ 1.27 (s, 9H), 1.75-1.88 (m, 1H), 2.40-2.48 (m, 1H),2.76-2.88 (m, 1H), 2.90-3.01 (m, 1H), 5.15 (m, 1H), 6.84 (br d, 1H),7.05 (d, 1H), 7.20, (m, 1H), 7.26 (s, 2H), 7.31 (s, 1H), 7.69 (d, 1H),8.1.1 (s, 1H), 8.72 (s, 1H); MS (ESI+): 349 (M+H)⁺; Elemental:Calculated for C₂₁H₂₄N₄O.HCl.0.17hexane: C, 66.19; H, 6.91; N, 14.02;Found: C, 66.11; H, 6.94; N, 13.96

EXAMPLE 13N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-1H-indazol-4-ylurea

The title compound was prepared using the procedure in Example 9, exceptusing methyl4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylateinstead of methyl4-[({[5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate.¹H NMR (DMSO-d₆) δ 1.27 (s, 9H), 1.75-1.88 (m, 1H), 2.40-2.48 (m, 1H),2.76-2.88 (m, 1H), 2.90-3.01 (m, 1H), 5.15 (m, 1H), 6.84 (br, 1H), 7.05(d, 1H), 7.20, (m, 1H), 7.26 (s, 2H), 7.31 (s, 1H), 7.69 (d, 1H), 8.17(s, 1H), 8.83 (s, 1H); MS (ESI+): 349 (M+H)⁺; Elemental: Calculated forC₂₁H₂₄N₄O.HCl: C, 65.53; H, 6.55; N, 14.56; Found: C, 65.29; H, 6.63; N,14.23.

EXAMPLE 14 methyl4-[({[5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate

The title compound was prepared using the procedure in Example 8D,except using 5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-ylamine insteadof 5-tert-butyl-2,3-dihydro-1H-inden-1-ylamine. ¹H NMR (DMSO-d₆) δ1.85-1.98 (m, 1H), 2.50-2.61 (m, 1H), 2.86-2.97 (m, 1H), 3.00-3.12 (m,1H), 4.04 (s, 3H), 5.29 (m, 1H), 6.85 (d, 1H), 7.51 (m, 1H), 7.57 (m,2H), 7.64 (s, 1H), 7.70 (d, 1H), 7.85 (d, 1H),8.42 (s, 1H), 8.96 (s,1H); MS (ESI+): 419 (M+H)⁺; Elemental: Calculated for C₂₀H₁₇N₄O₃F₃: C,57.42; H, 4.10; N, 13.39; Found: C, 57.44; H, 4.21; N, 13.03.

EXAMPLE 15N-1H-indazol-4-yl-N′-[5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]urea

The title compound was prepared using the procedure in Example 9, exceptusing methyl4-[({[5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylateinstead of methyl4-[({[5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate.¹H NMR (DMSO-d₆) δ 1.06 (t, 2.4H, EtOH), 1.82-1.94 (m, 1H), 2.52-2.60(m, 1H), 2.85-2.97 (m, 1H), 2.98-3.10 (m, 1H), 3.44 (q, 1.6H, EtOH),5.28 (m, 1H), 7.08 (m, 2H), 7.21 (m, 1H), 7.56 (m, 2H), 7.63 (s, 1H),7.69 (d, 1H), 8.17 (s, 1H), 8.91 (s, 1H); MS (ESI+) 361 (M+H)⁺;Elemental: Calculated for C₁₈H₁₅N₄OF₃.HCl.0.8EtOH.0.1H₂O: C, 54.06; H,4.86; N, 12.87; Found: C, 54.02; H, 4.58; N, 12.62.

EXAMPLE 16 methyl4-({[(5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylateExample 16A 5′-piperidin-1-ylindan-1-one

5-Fluoroindan-1-one (5 g, 33.3 mmol) and piperidine (8.52 g, 100 mmol,10 ml) were dissolved in pyridine (20 ml) and heated to reflux for 3hours. The reaction mixture was cooled, the solvent removed undervacuum, and the residue taken in diethyl ether. The ether solution waswashed with 1N aqueous sodium hydroxide and with water, dried withmagnesium sulfate, filtered, and the filtrate was removed under vacuumto provide the title compound which was used without furtherpurification. ¹H NMR (CDCl₃) δ 1.67 (m, 6H), 2.63 (m, 2H), 3.02 (m, 2H),3.40 (m, 4H), 6.78 (d, 1H), 6.86 (dd, 1H), 7.62 (d, 1H); MS (DCI) 216(M+H)⁺.

Example 16B 5-piperidin-1-ylindan-1-one O-methyloxime

5-Piperidin-1-ylindan-1-one (4.31 g, 20 mmol) in pyridine (20 ml) wastreated with methoxyamine hydrochloride (1.84 g, 22 mmol). Afterstirring at ambient temperature for 40 hours, the solvent was removedunder vacuum and the residue taken in water and extracted with diethylether. The combined organic layers were washed with water, dried withmagnesium sulfate, filtered, and the filtrate was removed under vacuumto provide the title compound which was used without furtherpurification. ¹H NMR (CDCl₃) δ 1.56-1.73 (m, 6H), 2.78-2.89 (m, 1H),2.91-3.02 (m, 1H), 3.20-3.30 (m, 2H), 3.95 (s, 3H), 6.78 (m, 1H), 6.84(m, 1H), 7.54 (d, 1H); MS (DCI): 245 (M+H)⁺.

Example 16C 5-piperidin-1-yl-2,3-dihydro-1H-inden-1-ylamine

5-Piperidin-1-ylindan-1-one O-methyloxime (2.95 g, 12 mmol), 10%palladium on carbon (1.45 g), and 20% ammonia in methanol (80 ml), wereplaced in a Parr apparatus which was charged with hydrogen to 60 psi.The mixture was shaken for 1 hour at ambient temperature and filtered.The filtrate was removed under vacuum to provide the title compoundwhich was used without further purification. ¹H NMR (CDCl₃) δ 1.53-1.60(m, 2H), 1.65-1.79 (m, 4H), 2.42-2.53 (m, 1H), 2.69-2.81 (m, 1H),2.86-2.96 (m, 1H), 3.12 (t, 4H), 4.31 (t, 1H), 6.82 (m, 2H), 7.20 (d,1H); MS (DCI) 217 (M+H)⁺.

Example 16D methyl 4-({[(5-piperidin-1-yl-2,3-dihydro-1H-inden-1-ylamino]carbonyl}amino)-1H-indazole-1-carboxylate

The title compound was prepared using the procedure in Example 8D,except using 5-piperidin-1-yl-2,3-dihydro-1H-inden-1-ylamine instead of5-tert-butyl-2,3-dihydro-1H-inden-1-ylamine. ¹H NMR (DMSO-d₆) δ1.48-1.66 (m, 6H), 1.75-1.89 (m, 1H), 2.39-2.47 (m, 1H), 2.70-2.82 (m,1H), 2.85-2.95 (m, 1H), 3.10 (m, 4H), 4.04 (s, 3H), 6.61 (d, 1H), 6.81(m, 2H), 7.12 (d, 1H), 7.49 (m, 1H), 7.68 (d, 1H), 7.88 (d, 1H), 8.38(s, 1H), 8.82 (s, 1H); MS (ESI+) 434 (M+H)⁺; Elemental: Calculated forC₂₄H₂₇N₅O₃.0.3CH₂Cl₂: C, 63.59; H, 6.06; N, 15.26; Found: C, 63.68; H,6.02; N, 15.14.

EXAMPLE 17N-1H-indazol-4-yl-N′-(5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl)urea

The title compound was prepared using the procedure in Example 9, exceptusing methyl4-({[(5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylateinstead of methyl4-[({[5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino})carbonyl)amino]-1H-indazole-1-carboxylate.¹H NMR (DMSO-d₆) δ 1.09 (t, 1.2H, Et₂O), 1.40-2.20 (br m, 7H), 2.52-2.59(m, 1H), 2.84-2.96 (m, 1H), 2.96-3.07 (m, 1H), 3.38 (q, 0.8H, Et2O),3.52 (m, 4H), 5.24 (m, 1H), 5.76 (s, 0.2H, CH₂Cl₂), 7.05 (d, 1H), 7.21(m, 1H), 7.33 (m, 1H), 7.50 (d, 1H), 7.65-7.77 (m, 3H), 8.29 (s, 1H),9.15 (s, 1H); MS (ESI+) 376 (M+H)⁺; Elemental: Calculated forC₂₂H₂₅N₅O.2HCl.0.1CH₂Cl₂.0.2Et₂O: C, 58.31; H, 6.24; N, 14.85; Found: C,58.22; H, 6.54; N, 15.00.

EXAMPLE 18 methyl4-({[(5-hexahydro-1H-azepin-1-yl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylateExample 18A 5-hexahydro-1H-azepin-1-ylindan-1-one

5-Fluoroindan-1-one (5 g, 33.3 mmol) and azepane (9.92 g, 100 mmol) weredissolved in pyridine (20 ml) and heated at reflux for 3 hours, stirredat ambient temperature for 16 hours, and then heated at reflux for anadditional 6 hours. The solvent was removed under vacuum and the residuepartitioned between methylene chloride and water. The organic layer waswashed with 1N aqueous sodium hydroxide, dried with magnesium sulfate,filtered, and the filtrate was concentrated under vacuum. The residuewas filtered through a pad of silica gel with 1:1 ethyl acetate:hexanes,and the solvent evaporated under vacuum to provide the title compoundwhich was used without further purification. ¹H NMR (CDCl₃) δ 1.56 (m,4H), 1.81 (m, 4H), 2.62 (m, 2H), 3.02 (m, 2H), 3.55 (t, 4H), 6.59 (d,1H), 6.68 (dd, 1H), 7.61 (d, 1H); MS (DCI) 230(M+H)⁺.

Example 18B 5-hexahydro-1H-azepin-1-ylindan-1-one O-methyloxime

The title compound was prepared using the procedure in Example 16B,except using 5-hexahydro-1H-azepin-1-ylindan-1-one instead of5-piperidin-1-ylindan-1-one. ¹H NMR (CDCl₃) δ 1.55 (m, 4H), 1.79 (m,4H), 2.77-2.88 (m, 1H), 2.92-3.00 (m, 1H), 3.48 (m, 2H), 3.94 (s, 3H),6.55 (m, 1H), 6.61 (m, 1H), 7.51 (d, 1H) MS (DCI): 259 (M+H)⁺.

Example 18C 5-hexahydro-1H-azepin-1-yl-2,3-dihydro-1H-inden-1-ylamine

The title compound was prepared using the procedure in Example 16C,except using 5-hexahydro-1H-azepin-1-ylindan-1-one O-methyloxime insteadof 5-piperidin-1-ylindan-1-one O-methyloxime. ¹H NMR (CDCl₃) δ 1.55 (m,4H), 1.60-1.74 (m, 1H), 1.77 (m, 4H), 2.41-2.52 (m, 1H), 2.69-2.69 (m,1H), 2.86-2.97 (m, 1H), 3.43 (t, 4H), 4.31 (t, 1H), 6.57 (m, 2H), 7.16(d, 1H); MS (DCI) 231 (M+H)⁺.

Example 18D methyl4-({[(5-hexahydro-1H-azepin-1-yl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylate

The title compound was prepared using the procedure in Example 16D,except using 5-hexahydro-1H-azepin-1-yl-2,3-dihydro-1H-inden-1-ylamineinstead of 5-piperidin-1-yl-2,3-dihydro-1H-inden-1-ylamine. ¹H NMR(DMSO-d₆) δ 1.17 (t, 0.21H, EtOAc), 1.45 (m, 4H), 1.71 (m, 4H),1.76-1.86 (m, 1H), 1.99 (s, 0.21H, EtOAc), 2.35-2.48 (m, 1H), 2.69-2.80(m, 1H), 2.84-2.95 (m, 1H), 3.45 (t, 4H), 4.03 (q, 0.14H, EtOAc), 4.04(s, 3H), 5.06 (m, 1H), 6.56 (m, 3H), 7.12 (d, 2H), 7.50 (m, 1H), 7.67(d, 1H), 7.89 (d, 1H), 8.38 (s, 1H). 8.79 (s, 1H); MS (ESI+) 448 (M+H)⁺;Elemental: Calculated for C₂₅H₂₉N₅O₃.0.07EtOAc: C, 66.92; H, 6.57; N,15.44; Found: C, 66.62; H, 6.85; N, 15.70.

EXAMPLE 19N-(5-hexahydro-1H-azepin-1-yl-2,3-dihydro-1H-inden-1-yl)-N′-1H-indazol-4-ylurea

The title compound was prepared using the procedure in Example 9, exceptusing methyl4-({[(5-hexahydro-1H-azepin-1-yl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylateinstead of methyl4-[({[5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate.¹H NMR (DMSO-d) δ 1.45 (m, 4H), 1.71 (m, 4H), 1.75-1.81 (m, 1H),2.38-2.45 (m, 1H), 2.86-2.93 (m, 1H), 3.45 (t, 4H), 5.07 (m, 1H), 6.58(m, 3H), 7.05 (d, 1H), 7.12 (d, 1H), 7.21 (m, 1H), 7.68 (d, 1H), 8.03(s, 1H), 8.51 (s, 1H), 12.97 (s, 1H); MS (ESI+) 390 (M+H)⁺.

EXAMPLE 20N-1H-indazol-4-yl-N′-[(1R)-5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl]urea

The title compound was obtained from the preparative chiral separation(ChiralPak AD, Hex(0.2% diethylamine):EtOH:MeOH=8:1:1) ofN-1H-indazol-4-yl-N′-(5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl)urea.¹H NMR (300 MHz, d₆-DMSO) 13.00 (broad s, 1H), 8.60 (s, 1H), 8.04 (s,1H), 7.67 (d, 1H), 7.18 (m, 2H), 7.03 (d, 1H), 6.80 (m, 2H), 6.66 (d,1H), 5.05 (m, 1H), 3.10 (m, 4H), 2.78 (m, 1H), 2.41 (m, 1H), 1.80 (m,1H), 1.68-1.45 (m, 7H); MS (DCI/NH₃) m/e 376 (M+H)⁺.

EXAMPLE 21N-1H-indazol-4-yl-N′-[(1S)-5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl]urea

The title compound was obtained from the preparative chiral separation(ChiralPak AD, Hex(0.2% diethylamine):EtOH:MeOH=8:1:1) ofN-1H-indazol-4-yl-N′-(5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl)urea.¹H NMR (300 MHz, d₆-DMSO) δ 13.00 (broad s, 1H), 8.61 (s, 1H), 8.04 (s,1H), 7.67 (d, 1H), 7.18 (m, 2H), 7.03 (d, 1H), 6.80 (m, 2H), 6.66 (d,1H), 5.05 (m, 1H), 3.10 (m, 4H), 2.78 (m, 1H), 2.41 (m, 1H), 1.80 (m,1H), 1.68-1.45 (m, 7H); MS (DCI(NH₃) m/e 376 (M+H)⁺.

EXAMPLE 22 isopropyl4-({[(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylateExample 22A isopropyl 4-nitro-1H-indazole-1-carboxylate

The title compound was prepared using the procedure in Example 8B,except using isopropyl chloroformate instead of methyl chloroformate.

Example 22B isopropyl 4-amino-1H-indazole-1-carboxylate

The title compound was prepared using the procedure in Example 8C,except using isopropyl 4-nitro-1H-indazole-1-carboxylate instead ofmethyl 4-nitro-1H-indazole-1-carboxylate.

Example 22C isopropyl4-({[(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylate

The title compound was prepared using the procedure in Example 8D,except using isopropyl 4-amino-1H-indazole-1-carboxylate instead ofmethyl 4-amino-1H-indazole-1-carboxylate. ¹H NMR (300 MHz, d₆-DMSO) 8.82(s, 1H), 8.40 (s, 1H), 7.90 (d, 1H), 7.68 (d, 1H), 7.50 (m, 1H), 7.29(d, 2H), 6.67 (d, 1H), 5.20 (m, 2H), 2.92 (m, 1H), 2.83 (m, 1H), 2.41(m, 1H), 1.84 (m, 1H), 1.40 (d, 6H), 1.30 (s, 9H); MS (DCI/NH₃) m/e 435(M+H)⁺; Anal. Calcd. For C₂₅H₃₀N₄O₃: C, 69.10; H, 6.96; N, 12.89. Found:C, 68.89; H, 6.90; N, 12.83.

EXAMPLE 23 isobutyl 4-({[(5-tert-butyl-2,3-dihydro-1H-inden-1-ylamino]carbonyl}amino)-1H-indazole-1-carboxylate Example 23A isobutyl4-nitro-1H-indazole-1-carboxylate

The title compound was prepared using the procedure in Example 8B,except using isobutyl chloroformate instead of methyl chloroformate.

Example 23B isobutyl 4-amino-1H-indazole-1-carboxylate

The title compound was prepared using the procedure in Example 8C,except using isobutyl 4-nitro-1H-indazole-1-carboxylate instead ofmethyl 4-nitro-1H-indazole-1-carboxylate.

Example 23C isobutyl4-({[(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}amino)-1H-indazole-1-carboxylate

The title compound was prepared using the procedure in Example 8D,except using isobutyl 4-amino-1H-indazole-1-carboxylate instead ofmethyl 4-amino-1H-indazole-1-carboxylate. ¹H NMR (300 MHz, d₆-DMSO) 8.82(s, 1H), 8.40 (s, 1H), 7.90 (d, 1H), 7.68 (d, 1H), 7.50 (m, 1H), 7.29(d, 2H), 6.70 (d, 1H), 5.19 (m, 1H), 4.23 (d, 2H), 2.88 (m, 1H), 2.80(m, 1H), 2.41 (m, 1H), 2.10 (m, 1H), 1.84 (m, 1H), 1.40 (d, 6H), 1.27(s, 9H), 1.00 (d, 6H); MS (DCI/NH₃) m/e 435 (M+H)⁺; Anal. Calcd. ForC₂₆H₃₂N₄O₃ 0.2 Et₂O: C, 69.47; H, 7.40; N, 12.09. Found: C, 69.49; H,7.72; N, 12.21.

It is understood that the Examples are merely illustrative and are notto be taken as limitations upon the scope of the invention, which isdefined solely by the appended claims and their equivalents. Variouschanges and modifications to the disclosed embodiments will be apparentto those skilled in the art. Such changes and modifications, includingwithout limitation those relating to the chemical structures,substituents, derivatives, intermediates, syntheses, formulations and/ormethods of use of the invention, may be made without departing from thespirit and scope thereof.

In Vitro Data

Determination of Inhibition Potencies

Dulbecco's modified Eagle medium (D-MEM)(with 4.5 mg/mL glucose) andfetal bovine serum were obtained from Hyclone Laboratories, Inc. (Logan,Utah). Dulbecco's phosphate-buffered saline (D-PBS)(with 1 mg/mL glucoseand 3.6 mg/l Na pyruvate)(without phenol red), L-glutamine, hygromycinB, and Lipofectamine™ were obtained from Life Technologies (GrandIsland, N.Y.). G418 sulfate was obtained from Calbiochem-NovabiochemCorp. (San Diego, Calif.). Capsaicin (8-methyl-N-vanillyl-6-nonenamide)was obtained from Sigma-Aldrich, Co. (St. Louis, Mo.). Fluo-4 AM(N-[4-[6-[(acetyloxy)methoxy]-2,7-difluoro-3-oxo-3H-xanthen-9-yl]-2-[2-[2-[bis[2-[(acetyloxy)methoxy]-2-oxyethyl]amino]-5-methylphenoxy]ethoxy]phenyl]-N-[2-[(acetyloxy)methoxy]-2-oxyethyl]-glycine,(acetyloxy)methyl ester) was purchased from Molecular Probes (Eugene,Oreg.).

The cDNAs for the human VR1 receptor were isolated by reversetranscriptase-polymerase chain reaction (RT-PCR) from human smallintestine poly A+RNA supplied by Clontech (Palo Alto, Calif.) usingprimers designed surrounding the initiation and termination codonsidentical to the published sequences (Hayes et al. Pain 88: 205-215,2000). The resulting cDNA PCR products were subcloned into pCIneomammalian expression vector (Promega) and fully sequenced usingfluorescent dye-terminator reagents (Prism, Perkin-Elmer AppliedBiosystems Division) and a Perkin-Elmer Applied Biosystems Model 373 DNAsequencer or Model 310 genetic analyzer. Expression plasmids encodingthe hVR1 cDNA were transfected individually into 1321N1 humanastrocytoma cells using Lipofectamine™. Forty-eight hours aftertransfection, the neomycin-resistant cells were selected with growthmedium containing 800 μg/mL Geneticin (Gibco BRL). Surviving individualcolonies were isolated and screened for VR1 receptor activity. Cellsexpressing recombinant homomeric VR1 receptors were maintained at 37° C.in D-MEM containing 4 mM L-glutamine, 300 μg/mL G418 (Cal-biochem) and10% fetal bovine serum under a humidified 5% CO₂ atmosphere.

The functional activity of compounds at the VR1 receptor was determinedwith a Ca²⁺ influx assay and measurement of intracellular Ca²⁺ levels([Ca²⁺]i). All compounds were tested over an 11-point half-logconcentration range. Compound solutions were prepared in D-PBS (4× finalconcentration), and diluted serially across 96-well v-bottom tissueculture plates using a Biomek 2000 robotic automation workstation(Beckman-Coulter, Inc., Fullerton, Calif.). A 0.2 μM solution of the VR1agonist capsaicin was also prepared in D-PBS. The fluorescent Ca²⁺chelating dye fluo-4 was used as an indicator of the relative levels of[Ca²⁺]i in a 96-well format using a Fluorescence Imaging Plate Reader(FLIPR)(Molecular Devices, Sunnyvale, Calif.). Cells were grown toconfluency in 96-well black-walled tissue culture plates. Then, prior tothe assay, the cells were loaded with 100 μL per well of fluo-4 AM (2μM, in D-PBS) for 1-2 hours at 23° C. Washing of the cells was performedto remove extracellular fluo-4 AM (2×1 mL D-PBS per well), andafterward, the cells were placed in the reading chamber of the FLIPRinstrument. 50 μL of the compound solutions were added to the cells atthe 10 second time mark of the experimental run. Then, after a 3 minutetime delay, 50 μL of the capsaicin solution was added at the 190 secondtime mark (0.05 μM final concentration) (final volume=200 μL) tochallenge the VR1 receptor. Time length of the experimental run was 240seconds. Fluorescence readings were made at 1 to 5 second intervals overthe course of the experimental run. The peak increase in relativefluorescence units (minus baseline) was calculated from the 190 secondtime mark to the end of the experimental run, and expressed as apercentage of the 0.05 μM capsaicin (control) response. Curve-fits ofthe data were solved using a four-parameter logistic Hill equation inGraphPad Prism® (GraphPad Software, Inc., San Diego, Calif.), and IC₅₀values were calculated.

The compounds of the present invention were found to be antagonists ofthe vanilloid receptor subtype 1 (VR1) receptor with IC_(50s) from about220 nM to about 1.0 nM. In a preferred range, compounds tested hadIC_(50s) from about 50 nM to about 1.0 nM.

In Vivo Data

Determination of Antinociceptive Effect

Experiments were performed on 400 adult male 129J mice (JacksonLaboratories, Bar Harbor, Me.), weighing 20-25 g. Mice were kept in avivarium, maintained at 22° C., with a 12 hour alternating light-darkcycle with food and water available ad libitum. All experiments wereperformed during the light cycle. Animals were randomly divided intoseparate groups of 10 mice each. Each animal was used in one experimentonly and was sacrificed immediately following the completion of theexperiment. All animal handling and experimental procedures wereapproved by an IACUC Committee.

The antinociceptive test used was a modification of the abdominalconstriction assay described in Collier, et al., Br. J. Pharmacol.Chemother. 32 (1968) 295-310. Each animal received an intraperitoneal(i.p.) injection of 0.3 mL of 0.6% acetic acid in normal saline to evokewrithing. Animals were placed separately under clear cylinders for theobservation and quantification of abdominal constriction. Abdominalconstriction was defined as a mild constriction and elongation passingcaudally along the abdominal wall, accompanied by a slight twisting ofthe trunk and followed by bilateral extension of the hind limbs. Thetotal number of abdominal constrictions was recorded from 5 to 20minutes after acetic acid injection. The ED_(50s) were determined basedon the i.p. injection.

The compounds of the present invention tested were found to haveantinociceptive effects with ED_(50s) from about 1 mg/kg to about 500mg/kg.

The in vitro and in vivo data demonstrates that compounds of the presentinvention antagonize the VR1 receptor and are useful for treating pain.

Compounds of the present invention are also useful for ameliorating orpreventing additional disorders such as, but not limited to, infammatorythermal hyperalgesia, bladder overactivity, and urinary incontinence asdescribed by Nolano, M. et al., Pain 81 (1999) 135; Caterina, M. J. andJulius, D., Annu. Rev. Neurosci. 24, (2001) 487-517; Caterina, M. J. etal., Science 288 (2000) 306-313; Caterina, M. J. et al., Nature 389(1997) 816-824; Fowler, C. Urology 55 (2000) 60; and Davis, J. et al.,Nature 405 (2000) 183-187.

The present invention also provides pharmaceutical compositions thatcomprise compounds of the present invention. The pharmaceuticalcompositions comprise compounds of the present invention that may beformulated together with one or more non-toxic pharmaceuticallyacceptable carriers.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracistemally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally,” as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous and intraarticular injection and infusion.

The term “pharmaceutically acceptable carrier,” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such a propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water, isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol and the like), vegetable oils (such as olive oil), injectableorganic esters (such as ethyl oleate) and suitable mixtures thereof.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compoundmay be mixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which maybe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) which is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the present invention can be employedin pure form or, where such forms exist, in pharmaceutically acceptablesalt, ester or prodrug form. The phrase “therapeutically effectiveamount” of the compound of the invention means a sufficient amount ofthe compound to treat disorders, at a reasonable benefit/risk ratioapplicable to any medical treatment. It will be understood, however,that the total daily usage of the compounds and compositions of thepresent invention will be decided by the attending physician within thescope of sound medical judgement. The specific therapeutically effectivedose level for any particular patient will depend upon a variety offactors including the disorder being treated and the severity of thedisorder; activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the patient; the time of administration, route of administration, andrate of excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed; and like factors well known in the medical arts.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. The phrase “pharmaceutically acceptable salt” means those saltswhich are, within the scope of sound medical judgement, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well-known in the art. Forexample, S. M. Berge et al. describe pharmaceutically acceptable saltsin detail in (J. Pharmaceutical Sciences, 1977, 66: 1 et seq). The saltscan be prepared in situ during the final isolation and purification ofthe compounds of the invention or separately by reacting a free basefunction with a suitable organic acid. Representative acid additionsalts include, but are not limited to acetate, adipate, alginate,citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,camphorate, camphorsulfonate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate),lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate,oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate, phosphate,glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, thebasic nitrogen-containing groups can be quaternized with such agents aslower alkyl halides such as, but not limited to, methyl, ethyl, propyl,and butyl chlorides, bromides and iodides; dialkyl sulfates likedimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides suchas, but not limited to, decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides; arylalkyl halides like benzyl and phenethylbromides and others. Water or oil-soluble or dispersible products arethereby obtained. Examples of acids which can be employed to formpharmaceutically acceptable acid addition salts include such inorganicacids as hydrochloric acid, hydrobromic acid, sulfuric acid, andphosphoric acid and such organic acids as acetic acid, fumaric acid,maleic acid, 4-methylbenzenesulfonic acid, succinic acid and citricacid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as, but not limited to,the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine. Pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas, but not limited to, lithium, sodium, potassium, calcium, magnesiumand aluminum salts and the like and nontoxic quaternary ammonia andamine cations including ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include ethylenediamine, ethanolamine, diethanolamine, piperidine,piperazine and the like.

The term “pharmaceutically acceptable prodrug” or “prodrug,” as usedherein, represents those prodrugs of the compounds of the presentinvention which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use. Prodrugs of the present invention may be rapidlytransformed in vivo to compounds of formula (I), for example, byhydrolysis in blood.

The present invention contemplates compounds of formula I formed bysynthetic means or formed by in vivo biotransformation of a prodrug.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms, such as hemi-hydrates. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water and ethanol among others are equivalent to the unsolvatedforms for the purposes of the invention.

The total daily dose of the compounds of this invention administered toa human or lower animal may range from about 0.01 to about 100mg/kg/day. For purposes of oral administration, more preferable dosescan be in the range of from about 0.1 to about 25 mg/kg/day. If desired,the effective daily dose can be divided into multiple doses for purposesof administration; consequently, single dose compositions may containsuch amounts or submultiples thereof to make up the daily dose.

1. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt or prodrug thereof.
 2. A method of treating a disorder byinhibiting vanilloid receptor subtype 1 in a mammal comprisingadministering a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt or prodrug thereof. 3.The method according to claim 1 wherein the disorder is pain.
 4. Themethod according to claim 1 wherein the disorder is bladderoveractivity.
 5. The method according to claim 1 wherein the disorder isurinary incontinence.
 6. The method according to claim 1 wherein thedisorder is inflammatory thermal hyperalgesia.